Phenyl and Benzodioxinyl Substituted Indazoles Derivatives

ABSTRACT

A compound of formula Ia: 
     
       
         
         
             
             
         
       
     
     The present invention relates to novel indazolyl derivatives, to pharmaceutical compositions comprising such derivatives, to processes for preparing such novel derivatives and to the use of such derivatives as medicaments

The present invention relates to novel indazolyl derivatives, topharmaceutical compositions comprising such derivatives, to processesfor preparing such novel derivatives and to the use of such derivativesas medicaments (for example in the treatment of an inflammatory diseasestate).

Sulphonamide derivatives are disclosed as anti-inflammatories in WO2004/019935 and WO 2004/050631. Pharmaceutically active sulphonamidesare also disclosed in Arch. Pharm. (1980) 313 166-173, J. Med. Chem.(2003) 46 64-73, J. Med. Chem. (1997) 40 996-1004, EP 0031954, EP1190710 (WO 200124786), U.S. Pat. No. 5,861,401, U.S. Pat. No.4,948,809, U.S. Pat. No. 3,992,441 and WO 99/33786.

It is known that certain non-steroidal compounds interact with theglucocorticoid receptor (GR) and, as a result of this interaction,produce a suppression of inflammation (see, for is example, U.S. Pat.No. 6,323,199). Such compounds can show a clear dissociation betweenanti-inflammatory and metabolic actions making them superior to earlierreported steroidal and non-steroidal glucocorticoids. The presentinvention provides further non-steroidal compounds as modulators (forexample agonists, antagonists, partial agonists or partial antagonists)of the glucocorticoid receptor. {Modulators of the glucocorticoidreceptor are disclosed in WO 2007/122165, WO 2008/076048 and WO2008/043788.}

Compared to the known compounds the compounds of the present inventionare contemplated to have improved properties such as selectivity,efficacy and/or crystallinity over the known compounds.

These new compounds are also contemplated to have an improved low Log Dand thus an improved distribution volume in vivo. The systemic exposureof the compounds is also expected to be improved. Further the compoundsare contemplated to have a lower melting point and improvedcrystallinity compared to the known compounds.

The compounds of the present invention are contemplated to have both animproved binding as well as improved crystallinity compared to the knowncompounds.

The present invention provides a compound of formula Ib:

wherein:A is C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄haloalkyl;R³ is C₅₋₁₀heteroaryl;W is phenyl substituted by —C(O)NR⁷R⁸;R⁷ is hydrogen or C₁₋₄alkyl;R⁸ is selected from hydrogen,C₁₋₆alkyl (optionally substituted by one or two groups selected fromhydroxyl, C₅₋₁₀aryl and C₅₋₁₀heteroaryl),C₃₋₇ cycloalkyl (optionally substituted by hydroxyl), andC₅₋₁₀heterocyclyl (optionally substituted by one or two groups selectedfrom hydroxyl and oxo);or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a compound of formulaIa

wherein:A is C₁₋₆alkyl, C₁₋₆alkoxy, C₃₋₇cycloalkyl, C₁₋₆haloalkyl,C₁₋₆allylthio, C₁₋₆alkylC(O), C₁₋₆alkyloxyC(O), NR⁵R⁶, NR⁵R⁶C(O) orC₅₋₁₀heteroaryl, all optionally substituted by one or more substituentsindependently selected from halo, cyano, hydroxyl, C₁₋₄alkyl, C₁₋₄alkoxyand C₁₋₄haloalkyl;R⁵ and R⁶ are independently selected from hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, C₁₋₆alkylC(O) and C₃₋₇cycloalkylC(O), or R⁵ and R⁶ mightform a ring with the nitrogen to which they are attached;R¹ is hydrogen, C₁₋₄alkyl, C₁₋₄hydroxyalkyl, C₁₋₄alkylthioC₁₋₄alkyl orC₁₋₄haloalkyl;R³ is C₅₋₁₀aryl, C₅₋₁₀arylC₁₋₄alkyl, C₅₋₁₀arylO, C₅₋₁₀arylC₁₋₄alkoxy,C₅₋₁₀aryloxyC₁₋₄alkyl, C₅₋₁₀heteroaryl, C₅₋₁₀heteroarylC₁₋₄alkyl,C₅₋₁₀heteroarylC₁₋₄alkoxy or C₅₋₁₀heteroaryoxyC₁₋₄alkyl, all of whichare unsubstituted or optionally substituted by one or more substituentsindependently selected from B;B is hydroxyl, halo, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₃hydroxyalkyl,C₁₋₄alkoxyC₁₋₄alkyl, C₃₋₆cycloalkyloxyC₁₋₄alkyl, C₃₋₆cycloalkyloxy,C₃₋₆cycloalkylthioC₁₋₄alkyl, C₃₋₆cycloalkylthio,C₁₋₃alkylS(O)_(k)C₁₋₄alkyl, C₁₋₃alkylS(O)_(k), C₁₋₄haloalkyl orC₁₋₄haloalkoxy, or B is one of the following groups which are linked toadjacent carbons on an aryl or heteroaryl ring(CH₂)_(t)OC₁₋₄alkylenylO(CH₂)_(v) or (CH₂)_(t)O(CH₂)_(v);k is 0, 1 or a compound according to claim 2;t and v are, independently, 0, 1, 2 or 3, and t and v are not both 0;

X is O or NH;

W is phenyl substituted by one or more substituents independentlyselected from (CH₂)_(n)C(O)NR⁷R⁸, (CH₂)_(n)NR⁹C(O)R⁸ or(CH₂)_(n)C(O)NR⁹(CR¹⁴R¹⁵)C(O)NR⁷R⁸; and W is optionally furthersubstituted by halogen or C₁₋₄alkyl;R⁷ is hydrogen or C₁₋₄ alkyl;R⁸ and R⁹ are, independently, hydrogen, C₁₋₄ alkyl (optionallysubstituted by one or two groups selected from hydroxyl, C₁₋₄ alkoxy,NH₂, oxo, C(O)NR¹⁰R¹¹, NR¹⁰C₁₋₄ alkyl, C(O)NR¹⁰C₁₋₄ alkyl, NR¹⁰C(O)C₁₋₄alkyl, C₁₋₄ alkylthio, C₅₋₁₀heterocyclyl, C₅₋₁₀aryl or C₅₋₁₀heteroaryl),C₃₋₇ cycloalkyl (optionally substituted by C(O)NH₂), C₅₋₁₀heterocyclyl,C₅₋₁₀aryl, C₅₋₁₀heteroaryl or C(O)NR¹⁰R¹¹; C₅₋₁₀aryl or C₅₋₁₀heteroarylare optionally substituted by halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, CF₃,OCF₃, hydroxy or cyano; heterocyclyl is optionally substituted by C₁₋₄alkyl, C₁₋₄ alkoxy(C₁₋₄ alkyl), oxo or hydroxyl;or R⁷ and R⁸, together with the nitrogen to which the are attached, forma 5- or 6-membered ring optionally comprising a second ring-nitrogenatom, the ring being optionally substituted by oxo, hydroxyl,C₁₋₄hydroxyalkyl, C₁₋₄ alkyl, C₁₋₄ alkoxy(C₁₋₄ alkyl) or(CH₂)_(p)C(O)NR¹²R¹³;R¹⁴ and R¹⁵ are, independently, hydrogen, C₁₋₄ alkyl or C₁₋₄hydroxyalkyl; or R¹⁴ and R¹⁵ join to form a C₃₋₆ cycloalkyl ring;R¹⁰, R¹¹, R¹² and R¹³ are, independently, hydrogen or C₁₋₄ alkyl;n and p are, independently, 0, 1, 2, 3 or 4; andY is hydrogen, halo, C₁₋₄alkyl or C₁₋₄haloalkyl;or a pharmaceutically acceptable salt thereof.

In one embodiment the present invention provides a compound of formulaIb wherein:

A is C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄haloalkyl;R³ is C₅₋₁₀heteroaryl;W is phenyl substituted by —C(O)NR⁷R⁸;R⁷ is hydrogen or C₁₋₄alkyl;R⁸ is selected from hydrogen,C₁₋₆alkyl (optionally substituted by one or two groups selected fromhydroxyl, C₅₋₁₀aryl and C₅₋₁₀heteroaryl),C₃₋₇ cycloalkyl, and C₅₋₁₀heterocyclyl (optionally substituted by one ortwo groups selected from hydroxyl and oxo);or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound offormula Ib wherein:

A is C₁₋₂haloalkyl;R³ is C₅₋₁₀heteroaryl;W is phenyl substituted by —C(O)NR⁷R⁸;R⁷ is hydrogen;R⁸ is selected from C₁₋₄alkyl (optionally substituted by hydroxyl,C₅₋₆aryl and C₅₋₆heteroaryl),C₅₋₆cycloalkyl (optionally substituted by hydroxyl), andC₅₋₆heterocyclyl (optionally substituted by oxo);or a pharmaceutically acceptable salt thereof.

In another embodiment the present invention provides a compound offormula Ib wherein:

A is C₁₋₂-fluoroalkyl;R³ is benzodioxinyl;W is phenyl substituted by —C(O)NR⁷R⁸;R⁷ is hydrogen;R⁸ is selected from methyl, ethyl, propyl or butyl (substituted by oneor two groups selected from hydroxyl, phenyl and pyridinyl),cyclopentyl, hydroxycyclopentyl, andoxidotetrahydrothiophenyl, dioxidotetrahydrothiophenyl,tetrahydrofuranyl or oxotetrahydrofuranyl;or a pharmaceutically acceptable salt thereof.

In a further embodiment the present invention provides a compound offormula Ia or Ib wherein A is fluoromethyl, difluoromethyl,trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl,fluoropropyl, difluoropropyl or trifluoropropyl. In one embodiments A isdifluoroethyl.

In another embodiment the present invention provides a compound offormula Ia wherein

R¹ is methyl or ethyl. In one embodiment R¹ is methyl.

In one embodiment the present invention provides a compound of formulaIa wherein X is O and Y is hydrogen.

In yet another embodiment the present invention provides a compound offormula Ia or Ib wherein A is difluoroethyl, R¹ is methyl, R³ isbenzodioxinyl, X is O, Y is hydrogen, W is phenyl substituted by—C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸ is selected from

C₁₋₄alkyl (optionally substituted by one or two groups selected fromhydroxyl, C₅₋₆aryl and C₅₋₆heteroaryl),C₅₋₆cycloalkyl (optionally substituted by hydroxyl), andC₅₋₆heterocyclyl (optionally substituted by oxo).or a pharmaceutically acceptable salt thereof.

In one embodiment the present invention provides a compound of formulaIa or Ib wherein

A is difluoroethyl, R¹ is methyl, R³ is benzodioxinyl, X is O, Y ishydrogen, W is phenyl substituted by —C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸is selected fromC₁₋₄alkyl (optionally substituted by one or two groups selected fromhydroxyl, C₅₋₆aryl and C₅₋₆heteroaryl),C₅₋₆cycloalkyl, andC₅₋₆heterocyclyl (optionally substituted by oxo).or a pharmaceutically acceptable salt thereof.

In yet a further embodiment the present invention provides a compound offormula Ia or Ib wherein A is difluoroethyl, R¹ is methyl, R³ isbenzodioxinyl, X is O, Y is hydrogen, W is phenyl substituted by—C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸ is selected from methyl or butyl(substituted by one or two groups selected from hydroxyl, phenyl andpyridinyl),

cyclopentyl, hydroxycyclopentyl, oxidotetrahydrothiophenyl,dioxidotetrahydrothiophenyl, tetrahydrofuranyl and oxotetrahydrofuranyl,is or a pharmaceutically acceptable salt thereof.

In one embodiment R⁸ is selected from methyl substituted by phenyl.

In another embodiment R⁸ is methyl substituted by pyridinyl.

In one embodiment R⁸ is methyl substituted by pyridin-3-yl orpyridin-4-yl.

In one embodiment R⁸ is butyl substituted by hydroxyl.

In another embodiment R⁸ is cyclopentyl.

In a further embodiment R⁸ is hydroxycyclopentyl.

In one embodiment R⁸ is oxidotetrahydrothiophenyl.

In another embodiment R⁸ is dioxidotetrahydrothiophenyl.

In a further embodiment R⁸ is tetrahydrofuranyl.

In one embodiment R⁸ is oxotetrahydrofuranyl.

In one embodiment R⁸ is selected from any one ofdioxidotetrahydrothiophen-3-yl], oxidotetrahydrothiophen-3-yl],tetrahydrofuran-3-yl, oxotetrahydrofuran-3-yl], cyclopentyl,hydroxycyclopentyl], hydroxybutyl, pyridin-4-ylmethyl,pyridin-3-ylmethyl, phenylmethyl.

In one embodiment the present invention provides a compound of formulaIa or Ib wherein A is difluoroethyl, R¹ is methyl, R³ is benzodioxinyl,X is O, Y is hydrogen, W is phenyl substituted by —C(O)NR⁷R⁸, R⁷ ishydrogen and R⁸ is dioxidotetrahydrothiophenyl.

In another embodiment the present invention provides a compound offormula Ia or Ib wherein A is difluoroethyl, R¹ is methyl, R³ isbenzodioxinyl, X is O, Y is hydrogen, W is phenyl substituted by—C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸ is cyclopentyl.

In yet another embodiment the present invention provides a compound offormula Ia or Ib wherein A is difluoroethyl, R¹ is methyl, R³ isbenzodioxinyl, X is O, Y is hydrogen, W is phenyl substituted by—C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸ is pyridinyl.

In a further embodiment the present invention provides a compound offormula Ia or Ib wherein A is difluoroethyl, R¹ is methyl, R³ isbenzodioxinyl, X is O, Y is hydrogen, W is phenyl substituted by—C(O)NR⁷R⁸, R⁷ is hydrogen and R⁸ is hydroxycyclopentyl.

In one embodiment R³ is 2,3-dihydro-1,4-benzodioxin-6-yl) or4H-1,3-benzodioxin-7-yl and the other substituents are selected from anycombination of substituents as defined above.

For the avoidance of doubt, the present invention relates to any onecompound falling within the scope of compounds of formula Ia or Ib.

One embodiment provides compounds selected from:

-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide    (E1),-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-tetrahydrofuran-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide,-   3-(5-({(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3RS)-tetrahydrofuran-3-yl]benzamide,-   3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[tetrahydrofuran-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-tetrahydrofuran-3-yl]benzamide,-   3-[5-({1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[tetrahydrofuran-3-yl]benzamide,-   N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,-   N-cyclopentyl-3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-cyclopentylbenzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-cyclopentylbenzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R)-2-hydroxycyclopentyl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(2S)-2-hydroxycyclopentyl]benzamide,-   3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2R)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2S)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2R)-2-hydroxycyclopentyl]benzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2R)-2-hydroxybutyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2S)-2-hydroxybutyl]benzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[2-hydroxybutyl]benzamide,-   3-(5-{(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide,-   3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide    (Isomer 1),-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1-oxidotetrahydrothiophen-3-yl]benzamide    (Isomer 2),-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-1-oxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[1-oxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide,-   3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-2-oxotetrahydrofuran-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3SR)-2-oxotetrahydrofuran-3-yl]benzamide,    and-   3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[2-oxotetrahydrofuran-3-yl]benzamide,    or a pharmaceutically acceptable salt thereof.

Another embodiment provides compounds selected from:

-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide    (E1),-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-tetrahydrofuran-3-yl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy]-1H-indazol-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[3S)-tetrahydrofuran-3-yl]benzamide,-   N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-cyclopentylbenzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2S)-2-hydroxycyclopentyl]benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2R)-2-hydroxybutyl]benzamide,-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide,-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide    (Isomer 1),-   3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide    (Isomer 2),-   3-[5-{[(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide,    and-   3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,    or a pharmaceutically acceptable salt thereof.

For the avoidance of doubt, the present invention relates to any onespecific compound mentioned in the list of compounds.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may be, butare not limited to methyl, ethyl, n-propyl, propyl, n-butyl, i-butyl,s-butyl, t-butyl, n-pentyl, i-pentyl, neo-pentyl, n-hexyl or i-hexyl.The term C₁₋₄ alkyl having 1 to 4 carbon atoms and may be but are notlimited to methyl, ethyl, n-propyl, i-propyl or t-butyl. The term “C₀”in C₀₋₄ alkyl refers to a situation where no carbon atom is present.

The term ‘alkyl’ and ‘alkylenyl’ refers to a straight or branched chainalkyl group linking two other atoms. It is, for example, CH₂ (methyl),CH₂CH₂ (ethyl), CH₂CH₂CH₂ or CH₂CH₃CH₂-(propyl) etc.

The term “alkoxy”, unless stated otherwise, refers to radicals of thegeneral formula —O—R, wherein R is selected from a hydrocarbon radical.The term “alkoxy” may include, but is not limited to methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy, iso-butoxy, cyclopropylmethoxy,allyloxy or propargyloxy.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted, partially or completely saturatedmonocyclic, bicyclic or bridged hydrocarbon ring system. The term“C₃₋₇cycloalkyl” may be, but is not limited to cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl as well as hydroxycyclopentyl.

In this specification, unless stated otherwise, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionallysubstituted, partially or completely saturated monocyclic, bicyclic orbridged hydrocarbon ring system having one or more heteroatomsindependently selected from O, N or S. The term “C₃₋₇heterocycloalkyl”may be, but is not limited to pyrrolidinyl, piperidinyl, piperazinyl,tetrahydrothiophenyl, oxidotetrahydrothiophenyl,dioxidotetrahydrothiophenyl tetrahydrofuranyl or oxotetrahydrofuranyl.

In this specification, unless stated otherwise, the term “a 5- or6-membered ring optionally comprising a second ring-nitrogen atom”refers to heterocycloalkyl as defined above and may be, but is notlimited to pyrrolidinyl, prolinamide or piperazinyl.

In this specification, unless stated otherwise, the terms “halo” and“halogen” may be fluorine (fluoro), iodine (iodo), chlorine (chloro) orbromine (bromo).

In this specification, unless stated otherwise, the term “haloalkyl”means an alkyl group as defined above, which is substituted with halo asdefined above. The term “C₁₋₆haloalkyl” may include, but is not limitedto fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl, trifluoroethyl, fluoropropyl, difluoropropyl ortrifluoropropyl, chloromethyl, dichloromethyl, trichloromethyl orfluorochloromethyl.

The term “C₁₋₃haloalkylO” or “C₁₋₃haloalkoxy” may include, but is notlimited to fluoromethoxy, difluoromethoxy, trifluoromethoxy,fluoroethoxy or difluoroethoxy.

In this specification, unless stated otherwise, the term “thioalkyl”means an alkyl group as defined above, which is substituted with sulphuratom. The term “C₁₋₆thioalkyl” may include, but is not limited tomethylsulfanyl, ethylsulfanyl or propylsulfanyl.

The term “cycloalkylthio” means a sulphur atom substituted with acycloalkyl as defined above such as for instance cyclopropylsulfanyl.

The term “C₁₋₄alkylthioalkyl” means a alkyl group with a sulphur atombetween the carbon atoms. The term “C₁₋₄alkylthioC₁₋₄alkyl” may include,but is not limited to ethylsulfanylmethyl.

In this specification, unless stated otherwise, the term “C₅₋₁₀aryl” oraryl refers to an aromatic or partial aromatic group having 5 to 10carbon atoms such as for example, phenyl or naphthyl. The term“C₅₋₄₀aryloxy” or “C₅₋₁₀arylO” refers to for example phenoxy.

In this specification, unless stated otherwise, the term“C₅₋₁₀heteroaryl” or heteroaryl refers to a mono- or bicyclic aromaticor partially aromatic ring with 5 to 10 atoms and containing one or moreheteroatoms independently selected from nitrogen, oxygen or sulphur.Heteroaryl is, for example, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl,furyl, thienyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl,1,2,4-triazolyl, pyridinyl, pyrimidinyl, indolyl, indazolyl, benzofuryl,benzothienyl, benzodioxinyl, dioxabicyclodecatrienyl, quinolinyl orisoquinolinyl.

When aryl (for example phenyl) or heteroaryl is substituted by(CH₂)_(t)OC₁₋₄alkylenylO(CH₂)_(v) or (CH₂)_(t)O(CH₂)_(v); wherein t andv are, independently, 0, 1, 2 or 3, but t and v are not both 0; thesesubstituents can be, for example, CH₂OCH₂O, OCH₂O, OCH₂CH₂O or OCH₂CH₂linking adjacent carbons on the aryl or heteroaryl ring.

For the avoidance of doubt a group R³ defined as C₅₋₁₀aryl e.g. phenyl,substituted with a group C₁₋₂alkylS(O)_(k) includes a phenyl substitutedwith methylsulphonyl group.

It will be appreciated that throughout the specification, the number andnature of substituents on rings in the compounds of the invention willbe selected so as to avoid sterically undesirable combinations.

Compounds of the present invention have been named with the aid ofcomputer software (ACDLabs 10.06/Name (IUPAC)).

Compounds of the invention may include an asymmetric centre and bechiral in nature. Where the compound is chiral, it may be in the form ofa single stereoisomer, such as a enantiomer, or it may be in the form ofmixtures of these stereoisomers in any proportions, including racemicmixtures. Therefore, all enantiomers, diastereomers, racemates andmixtures thereof are included within the scope of the invention. Thevarious optical isomers may be isolated by separation of a racemicmixture of the compounds using conventional techniques, for example,fractional crystallisation, or HPLC. Alternatively the optical isomersmay be obtained by asymmetric synthesis, or by synthesis from opticallyactive starting materials.

Compounds of the invention may be converted to a pharmaceuticallyacceptable salt thereof, such as an acid addition salt such as ahydrochloride, hydrobromide, phosphate, sulphate, acetate, ascorbate,benzoate, fumarate, hemifumarate, furoate, succinate, maleate, tartrate,citrate, oxalate, xinafoate, methanesulphonate, p-toluenesulphonate,benzenesulphonate, ethanesulphonate, 2-naphthalenesulfonate,mesytilenesulfonate, nitric acid, 1,5-naphthalene-disulphonate,p-xylenesulphonate, aspartate or glutamate. They may also include basicaddition salts such as an alkali metal salt for example sodium orpotassium salts, an alkaline earth metal salt for example calcium ormagnesium salts, a transition metal salt such as a zinc salt, an organicamine salt for example a salt of triethylamine, diethylamine,morpholine, N-methylpiperidine, N-ethylpiperidine, piperazine, procaine,dibenzylamine, N,N-dibenzylethylamine, choline or 2-aminoethanol oramino acids for example lysine or arginine.

The compounds of the invention, or a pharmaceutically acceptable saltthereof, may exist in solvated, for example hydrated, as well asunsolvated forms, or as cocrystals and the present invention encompassesall such forms.

Process

The compounds of the invention can be prepared using or adapting methodsdisclosed in the art, or by using or adapting the method disclosed inthe Example below. Starting materials for the preparative methods areeither commercially available or can be prepared by using or adaptingliterature methods.

A process for the synthesis of a compound of formula Ia or Ib cancomprise using an acid/amine coupling reaction disclosed in WO2007/122165, WO 2008/043788 or WO 2008/076048. For example using as anintermediate a compound of formula (Ic) or (Id):

wherein R¹, R³, X and Y are defined as above, and Z is A-C(O) orA-S(O)₂. A compound of the invention can be prepared if an acid offormula (Ic) is reacted with an amine of formula HNR⁷R⁸ orHNR⁹(CR¹⁴R¹⁵)C(O)NR⁷R⁸. Alternatively, a compound of the invention canbe prepared by reaction of an amine of formula (Id) with an acid asdefined by HOC(O)R⁸. The compounds of formula (Ic) and (Id) can besynthesised from protected to precursors such as alkylesters for thesynthesis of (Ic), or from an N-protected precursor of NR⁹H such asNR⁹BOC or N₃ for the preparation of (Id).

One embodiment relates to a process for the preparation of compounds offormula Ia or Ib by coupling a compound of formula (II):

with acylation reagents of formula (IIIa), (IIIb) or (IIIc)

wherein R¹, R³, A, X and Y are defined above, W is as defined above orcan be a group that can be converted into W as defined above, and L¹ isa leaving group {such as halogen (for example chloro) or, when L¹═OH, aleaving group generated by reaction of a coupling reagent (such as HATUwith a carboxylic acid)}. The reaction may be performed in a suitablesolvent (such as pyridine, THF or DMF), in the presence of a suitablebase (such as a tri(C₁₋₆ alkyl)amine, for example diisopropylethylamine,or pyridine) and at a suitable temperature (such as −10° to 50° C.).

A compound of formula (II) can be prepared according to step a, b or c.

a) A compound of formula (II) can be prepared by coupling a compound offormula (IV)

wherein W and Y are as defined above and L² is a leaving group (such ashalogen or triflate) with a compound of formula (V)

wherein R¹ and X are defined above and G corresponds to R³ or aprotected precurser to R³. The reaction can be performed in a suitablesolvent (such as an aromatic solvent, for example toluene) or a polar,aprotic solvent, such as DMF or butyronitril, in the presence of asuitable base (such as a alkali metal alkoxide (for example sodiumtert-butoxide) or, cesium carbonate, such as mediated by a suitablemetal catalyst such as Copper(I) iodide at a suitable temperature (forexample in the range 80° to 120° C.).

Or,

is b) A compound of formula (II) can be prepared by reacting a compoundof formula (VII)

with a compound of formula (VIII)

wherein R¹, X, W and Y are defined above, G corresponds to R³ or aprotected precurser to R³, and L³ is a leaving group (such as halogen,mesylate or tosylate). The reaction can be performed in a suitablesolvent (such as DCM, DMF or acetonitrile), in the presence of asuitable base (such as an alkali metal carbonate, for example cesiumcarbonate or potassium carbonate) at a suitable temperature (for examplein the range −10 to 50° C.), followed by a subsequent reductiveamination step using or adopting literature methods.

Or,

c) a compound of formula (II) may be prepared by reacting a compound offormula (VIII) with a compound of formula (IX)

wherein R¹ and R³ are as defined above, and PG is a suitable protectinggroup such as BOC, mesyl or tosyl or related carbonyl- or sulfonylresidues. The reaction can be performed in a suitable solvent such asDCM or toluene in the presence of a suitable base such as NaH or KOtBu,followed by a deprotection step using or adopting literature methods.

As a specific case of a compound of formula (V), a compound of formula(X) might be used to prepare a compound of formula (II)

wherein R¹ and G are defined as in compounds of formula (V).

Compounds of formula (X) may be prepared by reacting a nucleophile G-Mwith a carbonyl compound of formula (XI) followed reduction andsubsequent deprotection of the intermediate of formula (XII)

wherein R¹, R³, G and PG are as defined above, and L is a leaving group(such as alkoxy, methoxy(methyl)amino), M is a metal such as Li orMg-halide. The addition of the nucleophile may be performed in asuitable aprotic solvent such as THF at moderate temperature between −10and 50° C. The following reduction and deprotection steps might becarried out by using or adopting literature methods.

Alternatively, compounds of formula (X) may be prepared by a reaction ofa nucleophile G-M with an aldehyde of formula (XIII) and a subsequentdeprotection.

wherein R¹, R³, G and PG are as defined above, and M is a metal such asan alkali metal (e.g. Li) or Mg-halide. The reaction may be performed byfollowing disclosed protocols for addition of carbanions to aldehydes.

Another way to prepare a compound of formula (X) is the reaction of anitroalkyle of formula (XIV) with an aldehyde of formula (XV), followedby reduction of the nitro function

wherein R¹, R³ and G are as defined above. Both steps may be carried outby following or adopting literature methods.

Medical Use

Because of their ability to bind to the glucocorticoid receptor thecompounds of the invention are useful as anti-inflammatory agents, andcan also display antiallergic, immunosuppressive and anti-proliferativeactions. Thus, a compound of formula Ia or Ib, or a pharmaceuticallyacceptable salt thereof can be used as a medicament for the treatment orprophylaxis of one or more of the following pathologic conditions(disease states) in a mammal (such as a human):

(i) Lung diseases, which coincide with inflammatory, allergic and/orproliferative processes:chronically obstructive lung diseases of any origin, mainly bronchialasthma, chronicobstructive pulmonary diseasebronchitis of different originsAdult respiratory distress syndrome (ARDS), acute respiratory distresssyndrome

Bronchiectases

all forms of restructive lung diseases, mainly allergic alveolitisall forms of pulmonary edema, mainly toxic pulmonary edemasarcoidoses and granulomatoses, such as Boeck's disease(ii) Rheumatic diseases/auto-immune diseases/degenerative jointdiseases, which coincide with inflammatory, allergic and/orproliferative processes:all forms of rheumatic diseases, for example rheumatoid arthritis, acuterheumatic fever, polymyalgia rheumatica, collagenoses, Behçet's diseasereactive arthritisinflammatory soft-tissue diseases of other originsarthritic symptoms in degenerative joint diseases (arthroses)traumatic arthritidescollagen diseases of other origins, for example systemic lupuserythematodes, discoid lupus erythematosus, sclerodermia, polymyositis,dermatomyositis, polyarteritis nodosa, temporal arteritisSjögren's syndrome, Still syndrome, Felty's syndrome

Vitiligo

Soft-tissue rheumatism(iii) Allergies, which coincide with inflammatory, allergic and/orproliferative processes:All forms of allergic reactions, for example Quincke's edema, insectbites, allergic reactions to pharmaceutical agents, blood derivatives,contrast media, etc., anaphylactic shock, urticaria, contact dermatitis(e.g. allergic and irritative), allergic vascular diseasesAllergic vasculitisinflammatory vasculitis(iv) Vascular inflammations (vasculitides)Panarteritis nodosa, temporal arteritis, erythema nodosumPolyarteris nodosaWegner's granulomatosisGiant-cell arteritis(v) Dermatological diseases, which coincide with inflammatory, allergicand/or proliferative processes:atopic dermatitis (mainly in children)exfoliative dermatitis,psoriasiserythematous diseases, triggered by different noxae, for exampleradiation, chemicals, burns, etc.acid burnsbullous dermatoses, such as, for example, autoimmune pemphigus vulgaris,bullous pemphigoiddiseases of the lichenoid group itching (for example of allergicorigins)all forms of eczema, such as, for example, atopic eczema or seborrhealeczemarosaceapemphigus vulgariserythema exudativum multiformeerythema nodosumbalanitisPruritis, such as, for example, allergic origin)Manifestation of vascular diseasesvulvitisinflammatory hair loss, such as alopecia areatacutaneous T-cell lymphomaRashes of any origin or dermatosesPsoriasis and parapsoriasis groupsPityriasis rubra pilaris(vi) Nephropathies, which coincide with inflammatory, allergic and/orproliferative processes:nephrotic syndromeall nephritides, such as, for example, glomerulonephritis(vii) Liver diseases, which coincide with inflammatory, allergic and/orproliferative processes:acute liver cell decomposition acute hepatitis of different origins, forexample virally-, toxically- or pharmaceutical agent-induced chronicallyaggressive and/or chronically intermittent hepatitis(viii) Gastrointestinal diseases, which coincide with inflammatory,allergic and/or proliferative processes:regional enteritis (Crohn's disease)

Gastritis

Reflux esophagitis ulcerative colitisgastroenteritis of other origins, for example native sprue(ix) Proctological diseases, which coincide with inflammatory, allergicand/or proliferative processes:anal eczemafissureshemorrhoidsidiopathic proctitis(x) Eye diseases, which coincide with inflammatory, allergic and/orproliferative processes:allergic keratitis, uvenitis iritisconjunctivitisblepharitisoptic neuritischorioiditissympathetic ophthalmia(xi) Diseases of the ear-nose-throat area, which coincide withinflammatory, allergic and/or proliferative processes:allergic rhinitis, hay feverotitis externa, for example caused by contact dermatitis, infection,etc.otitis media(xii) Neurological diseases, which coincide with inflammatory, allergicand/or proliferative processes:cerebral edema, mainly tumor-induced cerebral edemamultiple sclerosisacute encephalomyelitisdifferent forms of convulsions, for example infantile nodding spasms

Meningitis

spinal cord injury

Stroke

(xiii) Blood diseases, which coincide with inflammatory, allergic and/orproliferative processes:acquired haemolytic anemiathrombocytopenia such as for example idiopathic thrombocytopeniaM. Hodgkins or Non-Hodgkins lymphomas,thrombocythemias,erythrocytoses(xiv) Tumor diseases, which coincide with inflammatory, allergic and/orproliferative processes:acute lymphatic leukaemiamalignant lymphomalymphogranulomatoseslymphosarcomaextensive metastases, mainly in breast and prostate cancers(xv) Endocrine diseases, which coincide with inflammatory, allergicand/or proliferative processes:endocrine orbitopathythyrotoxic crisisde Quervain's thyroiditisHashimoto's thyroiditis

Hyperthyroidism

Basedow's diseaseGranulomatous thyroiditisLymphadenoid goiter(xvi) Transplants, which coincide with inflammatory, allergic and/orproliferative processes;(xvii) Severe shock conditions, which coincide with inflammatory,allergic and/or proliferative processes, for example anaphylactic shock(xviii) Substitution therapy, which coincides with inflammatory,allergic and/or proliferative processes, with:innate primary suprarenal insufficiency, for example congenitaladrenogenital syndrome acquired primary suprarenal insufficiency, forexample Addison's disease, autoimmune adrenalitis, meta-infective,tumors, metastases, etc.innate secondary suprarenal insufficiency, for example congenitalhypopituitarism acquired secondary suprarenal insufficiency, for examplemeta-infective, tumors, etc.(xix) Emesis, which coincides with inflammatory, allergic and/orproliferative processes: for example in combination with a5-HT₃-antagonist in cytostatic-agent-induced vomiting.(xx) Pains of inflammatory origins, e.g., lumbago

Without prejudice to the foregoing, the compounds of the invention canalso be used to treat disorders such as: diabetes type I(insulin-dependent diabetes), Guillain-Barré syndrome, restenoses afterpercutaneous transluminal angioplasty, Alzheimer's disease, acute andchronic pain, arteriosclerosis, reperfusion injury, thermal injury,multiple organ injury secondary to trauma, acute purulent meningitis,necrotizing enterocolitis and syndromes associated with hemodialysis,leukopheresis, granulocyte transfusion, Conies Syndrome, primary andsecondary hyperaldosteronism, increased sodium retention, increasedmagnesium and potassium excretion (diuresis), increased water retention,hypertension (isolated systolic and combined systolic/diastolic),arrhythmias, myocardial fibrosis, myocardial infarction, Bartter'sSyndrome, disorders associated with excess catecholamine levels,diastolic and systolic congestive heart failure (CHF), peripheralvascular disease, diabetic nephropathy, cirrhosis with edema andascites, oesophageal varicies, muscle weakness, increased melaninpigmentation of the skin, weight loss, hypotension, hypoglycemia,Cushing's Syndrome, obesity, glucose intolerance, hyperglycemia,diabetes mellitus, osteoporosis, polyuria, polydipsia, inflammation,autoimmune disorders, tissue rejection associated with organ transplant,malignancies such as leukemias and lymphomas, rheumatic fever,granulomatous polyarteritis, inhibition of myeloid cell lines, immuneproliferation/apoptosis, HPA axis suppression and regulation,hypercortisolemia, modulation of the Th1/Th2 cytokine balance, chronickidney disease, hypercalcemia, acute adrenal insufficiency, chronicprimary adrenal insufficiency, secondary adrenal insufficiency,congenital adrenal hyperplasia, Little's syndrome, systemicinflammation, inflammatory bowel disease, Wegener's granulomatosis,giant cell arthritis, osteoarthritis, angioneurotic edema, tendonitis,bursitis, autoimmune chronic active hepatitis, hepatitis, cinhosis,panniculitis, inflamed cysts, pyoderma gangrenosum, eosinophilicfasciitis, relapsing polychondritis, sarcoidosis Sweet's disease, type 1reactive leprosy, capillary hemangiomas, lichen planus, erythema nodosumacne, hirsutism, toxic epiderrnal necrolysis, erythema multiform,psychoses, cognitive disorders (such as memory disturbances) mooddisorders (such as depression and bipolar disorder), anxiety disordersand personality disorders.

As used herein the term “congestive heart failure” (CHF) or ‘congestiveheart disease” refers to a disease state of the cardiovascular systemwhereby the heart is unable to efficiently pump an adequate volume ofblood to meet the requirements of the body's tissues and organ systems.Typically, CHF is characterized by left ventricular failure (systolicdysfunction) and fluid accumulation in the lungs, with the underlyingcause being attributed to one or more heart or cardiovascular diseasestates including coronary artery disease, myocardial infarction,hypertension, diabetes, valvular heart disease, and cardiomyopathy. Theterm “diastolic congestive heart failure” refers to a state of CHFcharacterized by impairment in the ability of the heart to properlyrelax and fill with blood. Conversely, the term “systolic congestiveheart failure” refers to a state of CHF characterized by impairment inthe ability of the heart to properly contract and eject blood.

As will be appreciated by one of skill in the art, physiologicaldisorders may present as a “chronic” condition, or an “acute” episode.The term “chronic”, as used herein, means a condition of slow progressand long continuance. As such, a chronic condition is treated when it isdiagnosed and treatment continued throughout the course of the disease.Conversely, the term “acute” means an exacerbated event or attack, ofshort course, followed by a period of remission. Thus, the treatment ofphysiological disorders contemplates both acute events and chronicconditions. In an acute event, compound is administered at the onset ofsymptoms and discontinued when the symptoms disappear.

In another aspect the present invention provides a compound of formulaIa or Ib, or a pharmaceutically acceptable salt thereof, for use intherapy (such as a therapy described above).

In yet another aspect the present invention provides the use of acompound of formula Ia or Ib, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofa glucocorticoid receptor mediated disease state (such as a diseasestate described above).

In a further aspect the invention provides the use of a compound offormula Ia or Ib, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of an inflammatorycondition (such as an arthritic).

In a further aspect the invention provides the use of a compound offormula Ia or Ib, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of a respiratorycondition.

In a still further aspect the invention provides the use of a compoundof formula Ia or Ib, or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for use in the treatment of asthma.

In another aspect the invention provides the use of a compound offormula Ia or Ib, or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of COPD.

In another aspect the present invention provides a compound of formulaIa or Ib, or a pharmaceutically acceptable salt thereof, for use intreating an inflammatory condition, a respiratory condition, asthmaand/or COPD.

The present invention further provides a method of treating aglucocorticoid receptor mediated disease state (such as a disease statedescribed above), an inflammatory condition, a respiratory condition,asthma and/or COPD, in a mammal (such as man), which comprisesadministering to a mammal in need of such treatment an effective amountof a compound of formula Ia or Ib, or a pharmaceutically acceptable saltthereof.

In the context of the present specification, the term “therapy” and“treatment” also includes prophylaxis and prevention unless there arespecific indications to the contrary. The terms “therapeutic” and“therapeutically” should be construed accordingly. In thisspecification, unless stated otherwise, the terms “inhibitor” and“antagonist” mean a compound that by any means, partly or completely,blocks the transduction pathway leading to the production of a responseby the agonist. An agonist may be a full or partial agonist.

The term “disorder”, unless stated otherwise, means any condition anddisease associated with glucocorticoid receptor activity.

Pharmaceutical Composition

In order to use a compound of formula Ia or Ib, or a pharmaceuticallyacceptable salt thereof, for the therapeutic treatment of a mammal, saidactive ingredient is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore another aspect the present invention provides a pharmaceuticalcomposition comprising a compound of formula Ia or Ib, or apharmaceutically acceptable salt thereof, (active ingredient) and apharmaceutically acceptable adjuvant, diluent or carrier. One embodimentrelates to the use of a pharmaceutical composition comprising a compoundof formula Ia or Ib, or a pharmaceutically acceptable salt thereof, fortreating a glucocorticoid receptor mediated disease state (such as adisease state described above), an inflammatory condition, asthma and/orCOPD.

A further aspect the present invention provides a process for thepreparation of said composition comprising mixing the active ingredientwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositioncan comprise from 0.05 to 99% w (percent by weight), for example from0.05 to 80% w, such as from 0.10 to 70% w (for example from 0.10 to 50%w), of active ingredient, all percentages by weight being based on totalcomposition.

A pharmaceutical composition of the present invention can beadministered in a standard manner for the disease condition that it isdesired to treat, for example by topical (such as to the lung and/orairways or to the skin), oral, rectal or parenteral administration.Thus, a compound of formula Ia or Ib, or a pharmaceutically acceptablesalt thereof, may be formulated into the form of, for example, anaerosol, a powder (for example dry or dispersible), a tablet, a capsule,a syrup, a granule, an aqueous or oily solution or suspension, an(lipid) emulsion, a suppository, an ointment, a cream, drops, or asterile injectable aqueous or oily solution or suspension.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule containing between 0.1 mg and 10 g of active ingredient.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous, intraarticular or intramuscularinjection.

In one embodiment a compound of formula Ia or Ib, or a pharmaceuticallyacceptable salt thereof, is administered orally.

In another embodiment a compound of formula Ia or Ib, or apharmaceutically acceptable salt thereof, is administered by inhalation.

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. Tablets may be enteric coated byconventional means, for example to provide a coating of celluloseacetate phthalate.

The invention further relates to a combination therapy or compositionwherein a compound of formula Ia or Ib, or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition comprising a compound offormula Ia or Ib, or a pharmaceutically acceptable salt thereof, isadministered concurrently (possibly in the same composition) orsequentially with one or more agents for the treatment of any of theabove disease states.

For example, for the treatment of rheumatoid arthritis, osteoarthritis,COPD, asthma or allergic rhinitis a compound of formula Ia or Ib, or apharmaceutically acceptable salt thereof, can be combined with one ormore agents for the treatment of such a condition. Where such acombination is to be administered by inhalation, then the one or moreagents is selected from the list comprising:

-   -   a PDE4 inhibitor including an inhibitor of the isoform PDE4D;    -   a selective β.sub2. adrenoceptor agonist such as metaproterenol,        isoproterenol, isoprenaline, albuterol, salbutamol, formoterol,        salmeterol, terbutaline, orciprenaline, bitolterol mesylate,        pirbuterol or indacaterol;    -   a muscarinic receptor antagonist (for example a M1, M2 or M3        antagonist, such as a selective M3 antagonist) such as        ipratropium bromide, tiotropium bromide, oxitropium bromide,        pirenzepine or telenzepine;    -   a modulator of chemokine receptor function (such as a CCR1        receptor antagonist);    -   an inhibitor of p38 kinase function;    -   an inhibitor of matrix metalloproteases, such as targeting        MMP-2, -9 or MMP-12; or,    -   an inhibitor of neutrophil serine proteases, such as neutrophil        elastase or proteinase 3.

In another embodiment of the invention where such a combination is forthe treatment of COPD, asthma or allergic rhinitis, a compound offormula Ia or Ib, or a pharmaceutically acceptable salt thereof, can beadministered by inhalation or by the oral route and the other agent,e.g. xanthine (such as aminophylline or theophylline) can beadministered by inhalation or by the oral route. A compound of formulaIa or Ib, or a pharmaceutically acceptable salt thereof, and the otheragent, e.g xanthine may be administered together. They may beadministered sequentially. Or they may be administered separately.

The following Examples illustrate the invention. The followingabbreviations are used in the Examples:

The following Examples illustrate the invention. The followingabbreviations are used in the Examples:

The following Examples illustrate the invention. The followingabbreviations are used in the Examples:

-   TFA Trifluoroacetic acid;-   THF Tetrahydrofuran-   DCM Dichloromethane-   HPLC High Performance Liquid Chromatography;-   LC/MS Liquid Column Chromatography/Mass Spectroscopy;-   GC Gas Chromatography-   SFC Supercritical Fluid Chromatography-   DMSO Dimethylsulfoxide;-   APCI-MS Atmospheric Pressure Chemical Ionisation Mass Spectroscopy;-   NMP 1-methyl-2-pyrrolidinone-   D N,N-diisopropylethylamine-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HBTU    2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium    hexafluorophosphate(V)-   r.t. Room temperature, which is a temperature in the range from of    16° C. to 25° C.

Synthetic Experimental General Methods

NMR spectra were recorded on a Varian Mercury-VX 300 MHz instrument or aVarian Inova 400 MHz instrument. The central peaks of chloroform-d (H7.27 ppm), acetone (H 2.05 ppm), dichloromethane-d2 (H 5.32 ppm) orDMSO-d₆ (H 2.50 ppm) were used as internal references. Alternatively,NMR spectra were recorded on a Varian Inova Unity 500 MHz instrument.Proton-NMR experiments were acquired using dual suppression of residualsolvent peak and H₂O.

The following methods was used for chiral SFC analysis:

Using an Analytical Method Development System from Thar Technologies,Inc. Using CO₂ as mobile phase with MeOH as modifier and pressure at 150bar. Columns used was kept at +37° C. by using an column oven. Detectionwas carried out on 254 nm.

Chiral SFC (method A): Chiralpak® AS, 0.46×25 cm column, 30% MeOH, 3mL/min.

Chiral SFC (method B): Chiralpak® IB, 0.46×25 cm column, 35% MeOH, 2mL/min.

The following method was used for LC/MS analysis:

Instrument Agilent 1100; Column Waters Symmetry 2.1×30 mm; Mass APCI;Flow rate 0.7 mL/min; Wavelength 254 nm; Solvent A: water+0.1% TFA;Solvent B: acetonitrile+0.1% TFA; Gradient 15-95% B 2.7 min, 95% B 0.3min.

The following method was used for GC-MS analysis:

Low resolution mass spectra and accurate mass determination wererecorded on a Hewlett-Packard GC. MS system equipped with EI ionisationchamber, 70 eV.

The following method was used for HPLC analysis:

LC Method A: HPLC method A was performed with Agilent 1100 seriesmachines on Kromassil© C18 Stun 3.0×100 mm column. Aqueous phase waswater/TFA (99.8/0.1) and organic phase was acetonitrile/TFA(99.92/0.08). Flow was 0.6 ml/min and gradient was set from 10 to 100%of organic phase during 20 minutes. Detection was carried out on 220,254 and 280 nm.

LC Method B: HPLC method B was performed with Agilent 1100 seriesmachines on XTerra® RP₈ 5 μm 3.0×100 mm column. Aqueous phase was 15 nMNH3 in water and organic phase was acetonitrile. Flow was 0.6 ml/min andgradient was set from 10 to 100% of organic phase during 20 minutes.Detection was carried out on 220, 254 and 280 nm.

Preparative HPLC system A: Column: XBridge C18, dimension (150×30 mm, 5μm packing), 20 ml/min solvent speed and gradient 20% to 90% MeCN (0.1TFA) in Water (0.1% TFA) over 20 min)

Differential Scanning Calorimetry: Using standard methods, for examplethose described in Höhne, G. W. H. et al (1996), Differential ScanningCalorimetry, Springer, Berlin, the calorimetric response of a testsample to increasing temperature was investigated using a TA InstrumentsQ2000 Modulated Temperature Differential Scanning Calorimeter (MTDSC)using a modulation of ±0.50° C. in intervals of 40 seconds and a ramprate of 5° C. per minute. Approximately 1 mg of test sample was placedin aluminium cups with lids (no crimping) under a nitrogen atmosphere.

It is well known that the DSC onset and peak temperatures may vary dueto the purity of the sample and instrumental parameters, especially thetemperature scan rate. A person skilled in the art can use routineoptimization/calibration to set up instrumental parameters for adifferential scanning calorimeter so that data comparable to the datapresented here can be collected.

Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received.

Intermediate I1 Isobutyl 3-(5-iodo-1H-indazol-1-yl)benzoate (I1)

A 50 mL.s flask was charged with sodium carbonate (0.700 g, 6.60 mmol),3-(5-iodo-1H-indazol-1-yl)benzoic acid (I1a) (2.185 g, 6 mmol) and NMP(15 mL) at 40° C. with magnetic stirring. After a couple of minutes1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) was added in one portion.After one hour at 40° C., the temperature was raised to 55° C. andanother portion of 1-bromo-2-methylpropane (0.971 mL, 9.00 mmol) wasadded. The stirring was continued overnight. After cooling, the reactionmixture was partitioned between water and ethyl acetate. The organicphase was washed twice with water, dried over Na₂SO₄, filtered andevaporated to dryness to afford the title compound as a syrup (2.5 g,99%). The product solidified to a beige material upon standing.

APCI-MS: m/z=421 [MH+]

¹H NMR (400 MHz, CDCl₃) δ 8.38 (1H, t), 8.19 (1H, d), 8.16 (1H, d), 8.07(1H, dt), 7.92 (1H, ddd), 7.70 (1H, dd), 7.64 (1H, t), 7.56 (1H, d),4.17 (2H, d), 2.12 (1H, m), 1.05 (6H, d).

LC (method A) rt=17.6 min

3-(5-Iodo-1H-indazol-1-yl)benzoic acid (I1a)

3-(2-(2-Fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (I1b, 3.47 g, 9mmol) and potassium tert. butoxide (2.3 g, 20.5 mmol) was stirred underargon atmosphere in NMP (45 mL) at 150° C. for 30 minutes. Aftercooling, the mixture was diluted with water (100 mL), acidified withaqueous HCl (1.7 M) and extracted trice with EtOAc. The combined organicphases were washed twice with water and then with brine. Evaporation ofthe organic phase afforded crude title compound (3.52 g, quant.) as alight brown, amorphous, gummy solid.

APCI-MS: m/z 365 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 13.2 (1H, b), 8.38 (1H, s), 8.33 (1H, s),8.24 (1H, bs), 8.04 (1H, bd), 7.97 (1H, d, further coupled), 7.81-7.68(3H).

3-(2-(2-Fluoro-5-iodobenzylidene)hydrazinyl)benzoic acid (I1b)

3-Hydrazinylbenzoic acid (1.52 g, 10 mmol)), 2-fluoro-5-iodobenzaldehyde(2.5 g, 10 mmol) and caesium carbonate (3.26 g, 10 mmol) were stirred inDMF (10 mL) at room temp under argon atmosphere for 2.5 h. Water (40 mL)was added and the clear solution was acidified with aqueous HCl (1.7 M).The beige-orange precipitate that formed was collected by, filtration,washed with water and dried in vacuo to give the title compound (3.75 g,98%).

APCI-MS: m/z 385 [MH⁺]

¹H-NMR (300 MHz, DMSO-d₆): δ 12.9 (1H, b), 10.85 (1H, s), 8.17 (1H, dd),7.94 (1H, s), 7.65 (1H, qd), 7.63-7.60 (2H), 7.40-7.31 (3H), 7.09 (1H,dd).

¹⁹F-NMR (300 MHz, DMSO-d₆, D₂O added): δ−123.4 (m).

Intermediate I2(1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-1-olhydrochloride. (I2)

5-6 N HCl in 2-Propanol (8 mL, 40-48 mmol) was added to tert-butyl(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate(I2a) (3.1 g, 10.02 mmol) in ethyl acetate (40 mL) at +40° C. andstirred at for 3 hours. The reaction mixture was allowed to reach roomtemperature and concentrated by evaporation. Ether was added and thesalt was collected by filtration and washed with ether. The salt wasfound to be hygroscopic. Yield 2.10 g (85%)

APCI-MS: m/z 210 [MH⁺—HCl]

¹H-NMR (300 MHz, DMSO-d₆): δ 8.01 (brs, 3H), 6.87-6.76 (m, 3H), 5.93(brd, 1H), 4.79 (brt, 1H), 4.22 (s, 4H), 3.32 (brm, 1H), 0.94 (d, 3H).

tert-butyl(1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropan-2-ylcarbamate.(I2a)

The diastereoselective catalytic Meerwein-Ponndorf-Verley reduction wasmade by the method described by Jingjun Yin et. al. J. Org. Chem. 2006,71, 840-843.

(S)-tert-butyl1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate (I2 b)(3.76 g, 12.23 mmol), aluminium isopropoxide (0.5 g, 2.45 mmol) and2-propanol (12 mL, 157.75 mmol) in toluene (22 mL) was stirred at +50°C. under argon for 16 hours. The reaction mixture was poured into 1M HCl(150 mL), the mixture was extracted with EtOAc (250 mL). The organicphase was washed with water (2×50 mL) and brine (100 mL), dried overNa₂SO₄, filtered and concentrated. The crude product was purified byflash-chromatography on silica using EtOAc:Hexane (1:2) as eluent.Fractions containing product was combined. Solvent was removed byevaporation to give the desired product as a colourless solid. Yield3.19 g (84%)

APCI-MS: m/z 236, 210, 192 [MH⁺-tBu-18, MH⁺-BOC, MH⁺-BOC-18]

¹H NMR (300 MHz, DMSO-d₆): δ 6.80-6.70 (m, 3H), 6.51 (d, 1H), 5.17 (d,1H), 4.36 (t, 1H), 4.19 (s, 4H), 3.49 (m, 1H), 1.31 (s, 9H), 0.93 (d,3H).

(S)-tert-butyl1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-oxopropan-2-ylcarbamate. (I2b)

A suspension of (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) inTHF (30 mL) was placed under a protective atmosphere of Argon and cooleddown to −15 to −20° C., isopropylmagnesium chloride, 2M in UV (6.5 mL,13.00 mmol) was added keeping the temperature below −10° C. The slurrystarted to dissolve, temperature was allowed to reach 0° C., a freshlyprepared solution of (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesiumbromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The temperature wasallowed to reach room temperature, the reaction mixture was stirred for17 hours. 1N HCl (300 mL) was cooled on icebath to +10° C., the reactionmixture was poured into the acidic water solution, TBME=tert-butylmethyl ether (300 mL) was added and the mixture was transferred to aseparation funnel. The waterphase was backextracted with TBME (200 mL).The ether phases were washed with water, brine and dried (Na₂SO₄).

The crude product was purified by flash chromatography usingTBME:Heptane=1:2 as eluent. Fractions containing the product wascombined and solvents was removed by evaporation to give the subtitlecompound as a slightly yellow sticky oil/gum. Yield 3.76 g (95%)

APCI-MS: m/z 208 [MH⁺-BOC]

¹H NMR (300 MHz, DMSO-d₆): δ 7.50 (dd, 1H), 7.46 (d, 1H), 7.24 (d, 1H),6.97 (d, 1H), 4.97 (m, 1H), 4.30 (m, 4H), 1.36 (s, 9H), 1.19 (d, 3H).

Intermediate I3(1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride(I3)

Tert-butyl(1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-1-hydroxypropan-2-ylcarbamate(I3b) (403 mg, 1.30 mmol) was dissolved in ethyl acetate (5 mL), 5-6 NHCl solution in 2-propanol (1.5 mL, 7.5-9 mmol) was added. The mixturewas stirred at +50° C. for 1.5 hours. The solvents was removed byevaporation, the residual sticky gum was treated with EtOAc andevaporated again to give a solid material that was suspended in MeCN andstirred for a few minutes. The solid colourless salt was collected byfiltration and was found to be somewhat hygroscopic, the salt wasquickly transferred to an dessicator and dried under reduced pressure.Yield 293 mg (92%)

APCI-MS: m/z 210 [MH⁺—HCl]

¹H NMR (300 MHz, DMSO-d₆) δ 8.07 (3H, s), 7.05 (1H, d), 6.92 (1H, dd),6.85 (1H, d), 6.03 (1H, d), 5.25 (2H, s), 4.87 (3H, m), 3.42-3.29 (1H,m), 0.94 (3H, d).

(4S,5R)-5-(4H-benzo[d][1,3]dioxin-7-yl)-4-methyloxazolidin-2-one (I3a)

A mixture of (1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-olhydrochloride (I3b) (120 mg, 0.49 mmol), DIEA (0.100 mL, 0.59 mmol) andCDI (90 mg, 0.56 mmol) in THF (2 mL) was stirred at room temperature for2 hours. The reaction mixture was concentrated by evaporation, theresidual material was partitioned between EtOAc and water, the organicphase was washed with 10% NaHSO₄, dried over MgSO₄, filtered andevaporated. The crude product was analysed by LC/MS and was consideredpure enough for further analysis by NMR. Yield 66 mg (57%)

The relative cis conformation of the product was confirmed by comparingthe observed 1H-NMR with the literature values reported for similarcyclisised norephedrine (Org. Lett. 2005 (07), 13, 2755-2758 andTerahedron Assym. 1993, (4), 12, 2513-2516). In a 2D NOESY experimentwas observed a strong NOE cross-peak for the doublett at 5.64 with themultiplet at 4.19 ppm, this also confirmed the relativecis-conformation.

APCI-MS: m/z 236 [MH⁺]

¹H NMR (400 MHz, CDCl₃) δ 6.99 (d, J=8.0 Hz, 1H), 6.88 (dd, J=8.0, 1.4Hz, 1H), 6.83 (s, 1H), 5.81 (brs, 1H), 5.64 (d, J=8.0 Hz, 1H), 5.26 (s,2H), 4.91 (s, 2H), 4.19 (m, 1H), 0.85 (d, J=6.4 Hz, 3H).

Tert-butyl(1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-1-hydroxypropan-2-ylcarbamate(I3b)

A mixture (S)-tert-butyl1-(4H-benzo[d][1,3]dioxin-7-yl)-1-oxopropan-2-ylcarbamate (I3c) (680 mg,2.21 mmol), triisopropoxyaluminum (140 mg, 0.69 mmol) and propan-2-ol (3mL, 38.9 mmol) in toluene (3 mL) was stirred at +65° C. for 15 hours.The reaction mixture was allowed to cool down and poured into 1M HCl (50mL) and extracted with EtOAc (2×50 mL). The organic phase was washedwith water, brine, dried over MgSO₄, filtered and solvents removed byevaporation to afford a crude product as a colourless solid. The crudeproduct was first purified by Flash chromatography, (solvent A=Heptane,solvent B=EtOAc+10% MeOH). An gradient of 10% B to 50% B in A was used.The obtained product was crystallised from DCM/Heptane to afford thesubtitle compound colourless needles. Yield 414 mg (60%)

APCI-MS: m/z 210 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 6.97 (1H, d), 6.88 (1H, d), 6.77 (1H, s),6.56 (1H, d), 5.27 (1H, d), 5.22 (2H, s), 4.83 (2H, s), 4.44 (1H, t),3.53 (1H, m), 1.32 (9H, s), 0.93 (3H, d).

(S)-Tert-butyl 1-(4H-benzo[d][1,3]dioxin-7-yl)-1-oxopropan-2-ylcarbamate(I3C)

7-Bromo-4H-benzo[d][1,3]dioxine (1 g, 4.65 mmol) was dissolved in THF (5mL) and added to magnesium (0.113 g, 4.65 mmol) under a protectiveatmosphere of argon, one small iodine crystal was added, the colouredsolution was heated with an heatgun in short periods to initiate thegrignard formation, when the iodine color vanished the reaction wasallowed to proceed at room temperature for 1.5 hours.

In a separate reaction tube was (S)-tert-butyl1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (1 g, 4.31 mmol)suspended in THF (5 mL) and cooled in an ice/acetone bath to below −5°C., isopropylmagnesium chloride, 2M solution in THF (2.5 mL, 5.00 mmol)was slowly added to form an solution. To this solution was added theabove freshly prepared grignard reagent. The mixture was allowed toreach room temperature and stirred for 4 hours. The reaction mixture wasslowly poured into ice-cold 150 mL 1M HCl, EtOAc (150 mL) was added andthe mixture was stirred for a few minutes and transferred to aseparation funnel. The organic phase was washed with water and brine,dried over MgSO4, filtered and concentrated. The obtained crude productwas further purified by flash chromatography using an prepacked 70 gsilica column with gradient of 10% TBME to 40% TBME in Heptane aseluent. The subtitle compound was obtained as a colourless solid. Yield790 mg (59%)

APCI-MS: m/z 208 [MH⁺-BOC]

¹H NMR (400 MHz, DMSO-d₆) δ 7.53 (1H, dd), 7.39 (1H, s), 7.30 (1H, d),7.22 (1H, d), 5.30 (2H, s), 4.98 (1H, m), 4.95 (2H, s), 1.35 (9H, s),1.20 (3H, d).

Intermediate I43-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoicacid (I4)

A solution of isobutyl3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate(I4a) (350 mg, 0.59 mmol) in THF (5 mL) and acetonitrile (2 mL) wastreated with 0.25 M NaOH (4.72 mL, 1.18 mmol). The mixture was stirredat ambient temperature for 23 hours, additional 1M NaOH (0.590 mL, 0.59mmol) was added and the mixture was stirred at +45° C. for 2 hours. Thereaction mixture was allowed to cool down and acidified to pH 2.5-3 byadding 1 N HCl. Addition of THF and MeCN until solution followed bypurification by HPLC, using an Kromasil 100-10-C18, 50×250 mm column, an30 min gradient from 50% to 90% MeCN in water+0.1% TFA in solvents withflow=40 mL/min and UV=254 nm to collect fractions. Fractions containingthe product was combined and freezedried. The material was redissolvedin tBuOMe, addition of Heptane gave precipitation, the formed slurry wasevaporated to afford the subtitle compound as a colourless solid. Yield315 mg (99%)

APCI-MS: m/z 538 [MH⁺]

¹H NMR (300 MHz, DMSO-d₆) δ 13.27 (1H, s), 8.66 (1H, d), 8.25 (1H, d),8.22 (1H, t), 8.00 (1H, ddd), 7.92 (1H, dt), 7.77 (1H, d), 7.69 (1H, t),7.22 (1H, dd), 7.14 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d), 4.22-4.11(5H, m), 1.54 (3H, t), 1.29 (3H, d).

Isobutyl3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate(I4a)

Isobutyl3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate(I4b) (0.5 g, 1.00 mmol), 2,2-difluoropropanoic acid (0.16 g, 1.45 mmol)and HBTU (0.567 g, 1.50 mmol) in DCM (4 mL) was treated with DIEA (0.696mL, 3.99 mmol), the mixture was stirred at ambient temperature for 1hour. The reaction was quenched by addition 10% NaHSO4 (aq), brine wasadded to help phase separation. The lower red DCM phase was separated,the waterphase was extracted with one portion of EtOAc, the combinedorganic solutions were dried over MgSO4 and filtered, solvents wasremoved by evaporation. Obtained a crude product as red oil. The crudematerial was further purified by flashchromatography using an 70 gprepacked silica column, an gradient of 0% to 50% EtOAc in Heptane wasapplied. Fractions with product was combined and solvents was removed byevaporation. An slightly yellow sticky oil was obtained after finalevaporation from DCM. Yield 540 mg (91%).

APCI-MS: m/z 594 [MH⁺]

¹H NMR (300 MHz, DMSO-d₆) δ 8.65 (1H, d), 8.26 (1H, d), 8.25 (1H, t),8.05 (1H, ddd), 7.95 (1H, dt), 7.78 (1H, d), 7.73 (1H, t), 7.22 (1H,dd), 7.14 (1H, d), 6.90-6.77 (3H, m), 5.17 (1H, d), 4.18 (4H, s), 4.15(1H, m), 4.12 (2H, d), 2.05 (1H, m), 1.55 (3H, t), 1.29 (3H, d), 0.99(6H, d).

Isobutyl3-(5-((1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoate(I4b)

A mixture of cesium carbonate (78 g, 240.00 mmol),(1R,2S)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propan-1-olhydrochloride (I4c) (19.66 g, 80.00 mmol), 2-(dimethylamino)acetic acid(4.12 g, 40.00 mmol) and copper(I) iodide (0.678 ml, 20.00 mmol) inbutyronitrile (188 ml) was stirred at 115° C. for 60 min under aprotective atmosphere of argon in 1 L round bottom-flask. A solution ofisobutyl 3-(5-iodo-1H-indazol-1-yl)benzoate (I1) (33.6 g, 80 mmol) inbutyronitrile (62.6 ml) was generated by heating at 80° C. for 20minutes in 250 mL round bottom-flask. The solution was pumped to theabove mixture within 2-3 minutes. The vessel was rinsed with furtherbutyronitrile (15.6 ml) which also was added. The grayish reactionmixture was sealed and stirred at 115° C. for 45 hours. The cooledreaction mixture was extracted between water (500 mL) and ethyl acetate(1.5 L). The organic phase was washed with water (3×700 mL) and thesolvents removed by reduced pressure affording 38 g of a gummy greenishresidue. The crude product dissolved in approx 60-70 mL DCM beforeloading the column, Flash chromatography on silica (d=13 cm, 1=18 cm)first using ethyl acetate:heptane 1:1 with 2% TEA (6 L), (so thestarting materials+the N-alkylated product eluted), ethylacetate:heptane 3:1 with 2% TEA (8 L) and then washed the columnwith—ethyl acetate (12 L) with 2% TEA, 600 ml, fractions collectedproduct mostly in fr 28-44, evaporated to dryness at 45° C. for 1 haffording 16.42 g of the product.

HNMR showed a pure product, contained some ethyl acetate (<5% byweight). HPLC purity>95%. Yield 16.42 g (41%)

APCI-MS: m/z 502 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.24 (2H, m), 8.05 (1H, ddd), 7.94 (1H, dt),7.77-7.72 (2H, m), 7.22 (1H, dd), 7.17 (1H, d), 6.88 (2H, m), 6.81 (1H,d), 4.97 (1H, d), 4.19 (4H, s), 4.12 (2H, d), 3.11 (1H, m), 2.05 (1H,m), 1.35 (2H, bs), 1.07 (3H, d), 0.99 (6H, d).

LC (method A) rt=12.3 min

LC (method B) rt=14.2 min

Intermediate 53-(5-((1R,2S)-1-(4H-Benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoicacid (I5)

Isobutyl3-(5-((1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoate(I5a) (398 mg, 0.67 mmol) was dissolved in methanol (3 mL) and THF (3.0mL). Lithium hydroxide (0.032 mL, 2.01 mmol) dissolved in water (2.5 mL)was added. A clear slightly pink solution was obtained. After 2 h thesolution was ice-cold. Ethyl acetate was added and then hydrochloricacid (1M) to acidic pH. The water phase was once more extracted withethyl acetate. The collected organic phases were dried over magnesiumsulfate and evaporated. It was dissolved in methanol and the solutionwas applied onto a 1 g SCX column. The methanol eluate (ca 15 mL) wasconcentrated. Freeze-drying from acetonitrile/water gave the titlecompound (362 mg, 100%).

APCI-MS: m/z 538 [MH⁺]

¹H NMR (400 MHz, CD₂Cl₂) δ 8.40 (1H, t), 8.05 (1H, dt), 8.02 (1H, d),7.98 (1H, ddd), 7.70 (1H, d), 7.65 (1H, t), 7.22 (1H, dd), 7.02 (1H, d),7.00 (1H, d), 6.91 (1H, s), 6.67 (1H, s), 5.22 (2H, q), 4.87 (2H, s),4.46-4.36 (1H, m), 1.75 (3H, t), 1.25 (3H, d).

Isobutyl3-(5-((1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoate(I5a)

A mixture of isobutyl3-(5-((1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propoxy)-1H-indazol-1-yl)benzoate(420 mg, 0.84 mmol) (I5b), 2,2-difluoropropanoic acid (213 mg, 1.94mmol) and HBTU (420 mg, 1.11 mmol) were suspended in dichloromethane (10mL). N-ethyl-N-isopropylpropan-2-amine (0.85 mL, 5.13 mmol) was addedand the mixture was stirred at room temperature overnight. Water (ca 10mL) was added to the solution. After stirring for some minutes themixture was added to a phase separator. The water phase was stirred withdichloromethane (5 mL) and added to the phase separator. The combinedorganic phases were concentrated to a brown oil. Purification by flashchromatography on silica (dichloromethane/ethyl acetate 10/1) gave thetitle compound as a white foam (400 mg, 80%).

APCI-MS: m/z 594 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (1H, d), 8.27-8.23 (2H, m), 8.07-8.03(1H, m), 7.95 (1H, d), 7.78 (1H, d), 7.73 (1H, t), 7.23 (1H, dd), 7.14(1H, d), 7.04-6.96 (2H, m), 6.86 (1H, s), 5.26-5.17 (3H, m), 4.82 (2H,s), 4.24-4.15 (1H, m), 4.12 (2H, d), 2.11-2.00 (1H, m), 1.56 (3H, t),1.30 (3H, d), 0.99 (6H, d)

Isobutyl3-(5-((1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propoxy)-1H-indazol-1-yl)benzoate(I5b)

A 250 mL one-neck round bottomed-flask with magnetic stirring and argonatmosphere was charged with cesium carbonate (30.3 g, 93.00 mmol),(1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propan-1-ol hydrochloride(I3) (7.37 g, 30.00 mmol), 2-(dimethylamino)acetic acid (1.547 g, 15.00mmol), copper(I) iodide (1.428 g, 7.50 mmol) and butyronitrile (72 mL)and heated at 110° C. for 30 min. A solution of isobutyl3-(5-iodo-1H-indazol-1-yl)benzoate (I1) (12.61 g, 30 mmol) inbutyronitrile (12.00 mL) was generated by heating at 80° C. for 10minutes. The solution was pumped to the above mixture within 3 minutes.The vessel was rinsed with further butyronitrile (6.00 mL) which alsowas added. The reaction mixture was sealed and stirred at 110° C. for 19h. The reaction mixture was cooled and extracted between water and ethylacetate (1 L). The organic phase was washed three times with water(3×500 mL), dried over magnesium sulfate and concentrated. The residuewas purified by flash chromatography on silica using ethylacetate:heptane 1:1 with 2% TEA followed by ethyl acetate:heptane 3:1with 2% TEA and finally with ethyl acetate with 2% TEA. This gave thetitle compound (5.1 g, 34%).

APCI-MS: m/z 502.2 [MH+]

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (1H, t), 8.23 (1H, s), 8.05 (1H, ddd),7.94 (1H, dt), 7.78-7.70 (2H, m), 7.24 (1H, dd), 7.17 (1H, d), 7.01 (2H,m), 6.89 (1H, s), 5.22 (2H, dd), 5.05 (1H, d), 4.83 (2H, ds), 4.11 (2H,d), 3.15 (1H, m), 2.05 (1H, m), 1.39 (2H, bs), 1.07 (3H, d), 0.98 (6H,d).

LC (method A) rt=10.6 min

LC (method B) rt=12.2 min

Intermediate I6 (S)-(−)-tetrahydrothiophene-3-amine-1,1-dioxidehydrochloride (I6)

(S)-(−)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (I6a) (7.08 g)was suspended in aqueous 5M HCl (250 mL). The mixture was heated at 130°C. for 13 hours. After cooling in an ice-bath solid benzoic acid wasremoved by filtration and washed with 1M aqueous HCl, the combinedfiltrates were evaporated to dryness. The residue was re-suspended in1,4-dioxane (40 mL), the colourless solid subtitle compound was isolatedby filtration, washed with dioxane (10 mL) and dried to constant weight.Yield 4.99 g (98%).

¹H NMR (400 MHz, D₂O): δ 4.12 (1H, pent, further coupled), 3.60 (1H,dd), 3.38 (1H, m), 3.27-2.15 (2H), 2.64 (1H, m), 2.21 (1H, m).

[α]_(D)−13.5° (c=1.1, H₂O)

(S)-(−)-N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (I6a)

(S)—N-(tetrahydrothiophen-3-yl)benzamide (I6b) (7.1 g) was dissolved inEtOAc (1.2 L). Sat. aqueous NaHCO₃ (0.6 L) was added.3-chlorobenzoperoxoic acid (77%, 27 g) was added in portions during 10min. Stirring was continued for 4 hours then dimethylsulphide (3.5 mL)was added and the stirring was continued for additional 100 min. tocompletely destroy excess m-chloroperbenzoic acid. The phases wereseparated, the organic phase was washed twice with water and evaporatedat reduced pressure. The colourless residue was re-crystallized fromEtOAc (˜350 mL) to yield pure subtitle compound (6.3 g). The mother liq.was evaporated and re-crystallized from EtOAc to give additional product(0.72 g).

Total yield 7.02 g (85.7%)

¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (1H, d), 7.88-7.84 (2H), 7.55 (1H, t,further coupled), 7.51-7.45 (2H), 4.70 (1H, sext.), 3.50 (1H, dd), 3.37(1H, ddd), 3.25-3.15 (1H m), 3.97 (1H, dd), 2.44 (1H, sext.), 2.28-2.16(1H, m).

[α]_(D)=−39.8° (c=1.0, MeOH)

(S)-(−)-N-(tetrahydrothiophen-3-yl)benzamide (I6b)

A 1.36M stock solution of HCl in AcOH was prepared from 100 ml AcOH, 11mL AcCl and 2.8 mL H₂O (slightly exothermic hydrolysis).

(S)-(−)-4-[2-(methylsulfanyl)ethyl]-2-phenyl-4,5-dihydro-1,3-oxazole(I6c) (1.7 g) was dissolved in 25 mL of acetic acid being 1.36 M inrespect to HCl. The solution was heated at 130° C. for 18 hs. GC-MS:shows complete reaction. Highest MS ion is 146 (M-61 fragment). Thereaction mixture was then cooled and freeze dried to afford the subtilecompound as a colourless fluffy solid. Yield 1.59 g (100%)

¹H NMR (400 MHz, DMSO-d₆): δ 8.41 (1H, d, NH), 7.86-7.82 (2H), 7.53 (1H,m), 7.49-7.43 (2H), 4.49 (1H, sext.), 3.03 (1H, dd), 2.96-2.88 (1H, m),2.88-2.80 (1H, m), 2.75 (1H, dd), 2.19-2.10 (1H, m), 2.07-1.97 (1H, m).

[α]_(D)−32.4° (c=0.95, MeOH)

(S)-(−)-4-[2-(methylsulfanyl)ethyl]-2-phenyl-4,5-dihydro-1,3-oxazole(I6c)

The described procedure is a somewhat modified, optimized andcomplementary one to the literature synthesis of3-aminotetrahydrotiophene enantiomer(s):

1. Dehmlow & Westerheide Synthesis 1992, 947-949 2. Ashton et al BioorgMed Chem Lett 17 (2007) 6779-6784

L-(S)-2-amino-4-(methylthio)butan-1-ol (10.0 g) and zinc(II) bromide(0.5 g) were mixed in benzonitrile (18 mL). The mixture was stirred at120° C. for 45 hours, the major part of the excess benzonitrile wasdistilled off by Kugelrohr distillation. The residue was diluted with asmall volume of CH₂Cl₂ and subjected to autoflash chromatography on SiO₂(330 g) using a gradient of 0-70% EtOAc in Heptane to afford thesubtitle compound as an oil. Yield 12.09 g (74%).

¹H NMR (300 MHz, DMSO-d₆): δ 7.81-7.75 (2H), 7.50-7.42 (1H, m),7.42-7.34 (2H), 4.42 (1H, dd), 4.29-4.18 (1H, m), 3.98 (1H, t),2.60-2.45 (2H), 1.99 (3H, s), 1.80-1.66 (2H).

[α]_(D)=−89.8° (c=1.5, EtOAc)

Intermediate 7 (R)-(+)-tetrahydrothiophene-3-amine-1,1-dioxidehydrochloride (I7)

The subtitle compound was prepared similarly as described for compound(I6), but starting from(R)—N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (I7a) (3.0 g). Yield2.10 g (98%).

[α]_(D)=12.5° (c=1.1, H₂O)

1H-NMR (400 MHz, DMSO-d6) δ 4.13 (1H, pent), 3.61 (1H, dd), 3.39 (1H,m), 3.27-3.17 (2H), 2.65 (1H, dtd), 2.29-2.16 (2H).

(R)—N-(1,1-dioxidotetrahydrothiophen-3-yl)benzamide (I7a)

The subtitle compound was prepared similarly as described for compound(I6a), but starting from (R)—N-(tetrahydrothiophen-3-yl)benzamide (I7b)(3.06 g). Yield 3.0 g (85.5%).

[α]_(D)+40.1° (c=1.0, MeOH)

H NMR (400 MHz, DMSO-d₆) δ 8.74 (1H, d), 7.88-7.83 (2H), 7.55 (1H, t,further coupled), 7.48 (2H, t, further coupled), 4.69 (1H, sext.), 3.50(1H, dd), 3.37 (1H, m), 3.20 (1H, ddd), 3.07 (1H, dd), 2.28-2.16 (1H,m).

(R)—N-(tetrahydrothiophen-3-yl)benzamide (I7b)

The subtitle compound was prepared similarly as described for compound(I6b), but starting from(R)-4-(2-(methylthio)ethyl)-2-phenyl-4,5-dihydrooxazole (I7c) (3.04 g).

Yield 2.78 g (98%).

[α]_(D)+32.2° (c=1.1, MeOH)

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (1H, d), 7.87-7.81 (2H, m), 7.53 (1H,m), 7.49-7.42 (2H, m), 4.49 (1H, sextet), 3.03 (1H, dd), 2.96-2.88 (1H,m), 2.88-2.80 (1H, m), 2.75 (1H, dd), 2.19-2.09 (1H, m), 2.07-1.96 (1H,m).

(R)-4-(2-(methylthio)ethyl)-2-phenyl-4,5-dihydrooxazole (I7c)

The subtitle compound was prepared similarly as described for compound(I6c), but starting from D-(R)-2-amino-4-(methylthio)butan-1-ol (7.75g). Yield 3.04 g (24%).

[α]_(D)=+89.8° (c=1.5, EtOAc)

¹HNMR (400 MHz, DMSO-d₆) δ 7.89-7.84 (2H, m), 7.57-7.51 (1H, m),7.50-7.44 (2H, m), 4.51 (1H, dd), 4.32 (1H, dq), 4.07 (1H, t), 2.60 (2H,m), 2.07 (3H, s), 1.81 (2H, m).

Intermediate 8 (S)-(−)-3-Aminotetrahydrothiphenesulphoxide hydrochloride(epimeric mixture) (I8)

(S)—N-(1-dioxidotetrahydrothiophen-3-yl)benzamide (I8a) (1.7 g, 7.61mmol) was dissolved in 5M aqueous HCl (140 mL) and stirred at (blocktemp.) 130° C. After 1 hour 15 minutes the temperature was lowered to+70° C. and the mixture was stirred at this temperature for additional11 hours 45 minutes, thereafter allowed to reach room temperature. Themixture was cooled in an ice-bath, crystalline precipitated benzoic acidwas removed by filtration, the filtrate was evaporated to leave stickygum. The material was dissolved in water and washed with 3×CH₂Cl₂, thewaterphase was evaporated, the residue was co-evaporated withEtOH-Toluene a couple of times and treated the semisolid residue withEtOH to form a suspension that was stirred at ambient temperature for 25minutes. The beige solid salt was collected by filtration to afford 200mg crude product (batch 1). Additional 82 mg (batch 2) materialcrystallised from the mother liquid. NMR analysis of the two batchesrevealed that racemization had taken place. No more purifications wasmade on these crude batches, they were both used as obtained.

batch 1:

¹H NMR (400 MHz, D₂O) δ 4.32 (0.88H, m), 4.14 (0.12H, m), 3.43-3.19 (2H,m), 3.14-2.95 (2H, m), 2.83-2.66 (1H, m), 2.58-2.47 (0.12H, m), 2.23(0.89H, m).

batch 2:

¹H NMR (400 MHz, D₂O) δ 4.32 (0.18H, m), 4.14 (0.82H, m), 3.43-3.18 (2H,m), 3.13-2.85 (2H, m), 2.81-2.65 (1H, m), 2.58-2.45 (0.81H, m), 2.22(0.19H, m).

(S)—N-(1-dioxidotetrahydrothiophen-3-yl)benzamide (I8a)

(S)-(−)-N-(tetrahydrothiophen-3-yl)benzamide (I6a) (2.81 g, 13.56 mmol)was dissolved in acetonitrile (150 mL). A heteropolyacid pyridinium saltcatalyst (360 mg) (PMo₁₁VO₄₀H₄×1.77 pyridine, prepared according toGustavo P. Romanelli et. al. Synlett 2005, 1, 75-78) was added followedby hydrogen peroxide (35%, 1.15 mL). The mixture was stirred at ambienttemperature, after 2.5 hours additional catalyst (100 mg) was added andthe reaction was allowed to proceed for another 2 hours. Me₂S (0.115 mL)was added, after 25 minutes the mixture was filtered and tested positivefor peroxide. Additional Me₂S (0.6 mL) was added and the mixture wasstirred over night at ambient temperature. Water (50 mL) and 2 g sodiumbisulphite was added and the mixture was stirred for 30 min. Solventswas evaporated to about half volume, diluted with water and extractedwith 3×EtOAc. The combined organic phases were washed with water andbrine and evaporated to leave a white solid. The obtained solid wasre-crystallized from EtOAc (˜70 mL) to yield 1.39 g of isomerically puresulphoxide (batch 1)

The mother liq. was evaporated and subjected to flash chromatography onSiO2 (20 g) 0-70% MeOH in EtOAc. Additional 365 mg (batch 2)isomerically pure sulphoxide was isolated. Also isolated were 145 mgmaterial containing an 3:2 epimeric mixture of the sulphoxide. The majorformed isomerically pure sulphoxide batches 1 and 2 were combined toafford a total of 1.75 g (58%)

[α]_(D)=−91.9° (c=1, MeOH)

¹H NMR (400 MHz, CD₃OD) δ 7.83 (2H, m), 7.54 (1H, m), 7.47 (2H, m), 4.90(1H, m), 3.52 (1H, dd), 3.19-3.02 (2H, m), 2.93 (1H, ddd), 2.66-2.53(2H, m).

¹³C NMR (100.586 MHz, CD₃OD) δ 169.41, 135.14, 132.84, 129.55, 128.33,59.09, 53.35, 52.81, 32.34.

EXAMPLE 1

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide(E1)

3-(5-((1R,2S)-2-(2,2-difluoropropanamido)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propoxy)-1H-indazol-1-yl)benzoicacid (I4) (106 mg, 0.20 mmol),(S)-(−)-tetrahydrothiophene-3-amine-1,1-dioxide hydrochloride (I6) (40mg, 0.23 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (2 mL) was treatedwith DIEA (0.138 mL, 0.79 mmol). The reaction mixture was stirred atambient temperature for 45 minutes. Water (10 mL) was added, the formedsuspension was stirred for 1 hour. The solid was collected byfiltration, washed with water and further purified by HPLC using anKromasil 100-10-C18, 50×250 mm column, an 30 min gradient from 50% to90% MeCN in water with flow=40 mL/min and UV=254 nm to collectfractions. Fractions containing the product was freezedried, theresulting solid was dissolved in MeOH and iso-Hexane was added. Thebiphasic mixture was evaporated to give an solid that was suspended iniso-Hexane containing a small volume of EtOAc, the suspension wasstirred at ambient temperature for 18 hours. The crystalline solid wascollected by filtration, washed with iso-Hexane and dried. Yield 77 mg(59%).

APCI-MS: m/z 655 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (1H, d), 8.65 (1H, d), 8.25 (1H, d),8.19 (1H, s), 7.92 (1H, d), 7.86 (1H, d), 7.77 (1H, d), 7.68 (1H, t),7.21 (1H, dd), 7.14 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d), 4.73 (1H,m), 4.24-4.11 (5H, m), 3.52 (1H, dd), 3.37 (1H, m), 3.20 (1H, m), 3.10(1H, dd), 2.45 (1H, m), 2.23 (1H, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt=9.94 min

LC (method B) rt=9.15 min

Chiral SFC (method A) rt=4.93 min

M.p.=180° C.

The compounds of Examples 2 to 24 were prepared by processes analogousto those described in Example 1 or by processes known in the art.

EXAMPLE 2

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide

APCI-MS: m/z 655 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (1H, d), 8.65 (1H, d), 8.25 (1H, s),8.19 (1H, s), 7.92 (1H, d), 7.85 (1H, d), 7.77 (1H, d), 7.68 (1H, t),7.21 (1H, dd), 7.14 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d), 4.72 (1H,m), 4.24-4.11 (5H, m), 3.52 (1H, dd), 3.38 (1H, m), 3.20 (1H, m), 3.10(1H, dd), 2.44 (1H, m), 2.23 (1H, ddd), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt=9.94 min

LC (Method B) rt=9.15 min

Chiral SFC (method A) rt=5.87 min

M.p.=218° C.

EXAMPLE 3

3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide

APCI-MS: m/z 655 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (1H, d), 8.71 (1H, d), 8.25 (1H, s),8.18 (1H, s), 7.91 (1H, d), 7.86 (1H, d), 7.78 (1H, d), 7.68 (1H, t),7.23 (1H, dd), 7.14 (1H, d), 7.00 (2H, q), 6.86 (1H, s), 5.26-5.17 (3H,m), 4.82 (2H, s), 4.78-4.67 (1H, m), 4.24-4.13 (1H, m), 3.52 (1H, dd),3.42-3.32 (1H, m), 3.25-3.16 (1H, m), 3.10 (1H, dd), 2.49-2.41 (1H, m),2.29-2.17 (1H, m), 1.56 (3H, t), 1.30 (3H, d).

LC (Method A, flow 1.0 mL/min) rt=10.15 min

LC (Method B, flow 1.0 mL/min) rt=9.76 min

M.p.=239° C.

EXAMPLE 4

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide

APCI-MS: m/z 655 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (1H, d), 8.71 (1H, d), 8.25 (1H, s),8.18 (1H, s), 7.91 (1H, d), 7.85 (1H, d), 7.78 (TH, d), 7.68 (1H, t),7.23 (1H, dd), 7.14 (1H, d), 7.00 (2H, q), 6.86 (1H, s), 5.26-5.17 (3H,m), 4.82 (2H, s), 4.78-4.67 (1H, m), 4.24-4.13 (1H, m), 3.52 (1H, dd),3.42-3.32 (1H, m), 3.25-3.16 (1H, m), 3.10 (1H, dd), 2.49-2.41 (1H, m),2.29-2.17 (1H, m), 1.56 (3H, t), 1.30 (3H, d).

LC (Method A, flow 1.0 mL/min) rt=9.80 min

LC (Method B, flow 1.0 mL/min) rt=8.76 min

M.p.=224° C.

EXAMPLE 5

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-tetrahydrofuran-3-yl]benzamide

APCI-MS: m/z 607 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆). δ 8.71 (1H, d), 8.65 (1H, d), 8.24 (1H, s),8.18 (1H, s), 7.90-7.84 (2H, m), 7.77 (1H, d), 7.65 (1H, t), 7.21 (1H,dd), 7.13 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d), 4.48 (1H, m),4.24-4.11 (5H, m), 3.90-3.81 (2H, m), 3.72 (1H, td), 3.61 (1H, dd), 2.16(1H, m), 1.94 (1H, m), 1.55 (3H, t), 1.29 (3H, d).

LC (Method A) rt=12.02 min

LC (Method B) rt=11.12 min

Chiral SFC (method B) rt=5.10 min

M.p.=175° C.

EXAMPLE 6

3-(5-{[1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide

APCI-MS: m/z 607 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (1H, d), 8.65 (1H, d), 8.24 (1H, s),8.18 (1H, s), 7.90-7.84 (2H, m), 7.77 (1H, d), 7.65 (1H, t), 7.21 (1H,dd), 7.13 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d), 4.48 (1H, m),4.23-4.10 (5H, m), 3.89-3.82 (2H, m), 3.72 (1H, td), 3.61 (1H, dd), 2.16(1H, m), 1.94 (1H, m), 1.55 (3H, t), 1.29 (3H, d).

LC (method A) rt=12.03 min

LC (method B) rt=11.13 min

Chiral SFC (method B) rt=4.71 min

M.p.=177° C.

EXAMPLE 7

N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide

APCI-MS: m/z 605 [MH⁺]

¹H-NMR (DMSO-d₆, 400 MHz) δ 8.65 (1H, d); 8.45 (1H, d); 8.24 (1H, d);8.15 (1H, t); 7.86-7.83 (2H, m); 7.75 (1H, d); 7.63 (1H, t); 7.20 (1H,dd); 7.13 (1H, d); 6.88-6.85 (2H, m); 6.81-6.79 (1H, m); 5.17 (1H, d);4.27-4.12 (6H, m); 1.93-1.85 (2H, m); 1.69 (2H, br.s); 1.59-1.49 (7H,m); 1.29 (3H, d).

LC (method A) rt=14.40 min

LC (method B) rt=13.24 min

M.p.=170° C.

EXAMPLE 8

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-cyclopentylbenzamide

APCI-MS: m/z 605 [MH⁺]

¹H-NMR (DMSO-d₆, 400 MHz) δ 8.71 (1H, d); 8.45 (1H, d); 8.23 (1H, s);8.14 (1H, t); 7.86-7.83 (2H, m); 7.75 (1H, d); 7.63 (1H, t); 7.22 (1H,dd); 7.13 (1H, d); 7.03-6.97 (2H, m); 6.86 (1H, s); 5.23-5.18 (3H, m);4.82 (2H, s); 4.28-4.15 (2H, m); 1.95-1.86 (2H, m); 1.73-1.65 (2H, m);1.60-1.50 (7H, m); 1.30 (3H, d).

LC (method A) rt=11.32 min

LC (method B) rt=10.47 min

M.p.=182° C.

EXAMPLE 9

3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]benzamide

APCI-MS: m/z 607 [MH⁺]

¹H NMR (400 MHz, DMSO-d₆) δ 8.74-8.67 (2H, m), 8.24 (1H, s), 8.18 (1H,s), 7.87 (2H, t), 7.77 (1H, d), 7.65 (1H, t), 7.22 (1H, dd), 7.13 (1H,d), 7.04-6.96 (2H, m), 6.86 (1H, s), 5.25-5.17 (3H, m), 4.82 (2H, s),4.53-4.44 (1H, m), 4.24-4.13 (1H, m), 3.90-3.81 (2H, m), 3.75-3.68 (1H,m), 3.61 (1H, dd), 2.21-2.11 (1H, m), 1.99-1.89 (1H, m), 1.56 (3H, t),1.30 (3H, d).

LC (method A) rt=11.88 min

LC (method B) rt=10.99 min

M.p.=192° C.

EXAMPLE 10

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide

APCI-MS: m/z 621 [MH+]

¹H NMR (300 MHz, DMSO-d₆, 1 proton signal covered by solvent) δ 8.65(1H, d), 8.22 (2H, d), 8.10 (1H, d), 7.87 (2H, m), 7.78 (1H, d), 7.64(1H, t), 7.20 (1H, dd), 7.13 (1H, d), 6.89-6.78 (3H, m), 5.17 (1H, d),4.72 (1H, d), 4.21-4.03 (6H, m), 1.77 (4H, m), 1.55 (5H, t), 1.29 (3H,d).

LC (method A): rt=11.82 min

LC (method B): rt=9.86 min

M.p.=165° C.

EXAMPLE 11

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2R)-2-hydroxybutyl]benzamide

APCI-MS: m/z 609 [MH+]

¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (1H, d), 8.57 (1H, t), 8.24 (1H, s),8.17 (1H, m), 7.86 (2H, m), 7.79 (1H, d), 7.64 (1H, t), 7.22 (1H, dd),7.13 (1H, d), 7.04-6.96 (2H), 6.86 (1H, s), 5.26-5.18 (3H), 4.82 (2H,s), 4.72 1H, d), 4.19 (1H, sext), 3.56 (1H, m), 3.37-3.27 (1H, partiallyobscured by solvent moisture signal), 3.23-3.14 (1H), 1.56 (3H, t), 1.47(1H, m), 1.37-1.22 (1H, partially obscured by methyl doublet), 1.30 (3H,d), 0.90 (3H, t).

HPLC method (A): rt=11.83 min

HPLC method (B): rt=10.26 min

M.p.=182° C.

EXAMPLE 12

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide

APCI-MS: m/z 628 [MH+]

1H NMR (400 MHz, DMSO-d₆) δ 9.24 (1H, t), 8.66 (1H, d), 8.57 (1H, d),8.46 (1H, dd), 8.24 (1H, s), 8.21 (1H, s), 7.89 (2H, m), 7.79 (1H, d),7.74 (1H, m), 7.67 (1H, t), 7.36 (1H, dd), 7.21 (1H, dd), 7.14 (1H, d),6.88-6.78 (3H, m), 5.17 (1H, d), 4.53 (2H, d), 4.25-4.09 (5H, m), 1.54(3H, t), 1.29 (3H, d).

LC (method A) rt=9.61 min

LC (method B) rt=9.58 min

M.p.=135° C.

EXAMPLE 13

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide

APCI-MS: m/z 628 [MH+]

1H NMR (400 MHz, DMSO-d6) δ 9.26 (1H, t), 8.71 (1H, d), 8.57 (1H, d),8.46 (1H, dd), 8.24 (1H, s), 8.22-8.19 (1H, m), 7.89 (2H, t), 7.80 (1H,d), 7.76-7.72 (1H, m), 7.67 (1H, s), 7.36 (1H, dd), 7.22 (1H, dd), 7.13(1H, d), 7.04-6.96 (2H, m), 6.86 (1H, s), 5.25-5.17 (3H, m), 4.82 (2H,s), 4.52 (2H, d), 4.24-4.13 (1H, m), 1.56 (3H, t), 1.30 (3H, d).

LC (method A) rt=9.86 min

LC (method B) rt=11.18 min

M.p.=159° C.

EXAMPLE 14

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide

APCI-MS: m/z 621 [MH+]

¹H NMR (400 MHz, DMSO-d6) δ 8.71 (1H, d), 8.23 (1H, s), 8.22 (1H, s),8.10 (1H, d), 7.89-7.83 (2H, m), 7.78 (1H, d), 7.64 (1H, t), 7.22 (1H,dd), 7.13 (1H, d), 7.04-6.97 (2H, m), 6.86 (1H, s), 5.25-5.18 (3H, m),4.82 (2H, s), 4.72 (1H, s), 4.24-4.14 (1H, m), 4.12-4.03 (2H, m),1.89-1.69 (4H, m), 1.64-1.44 (5H, m), 1.30 (3H, d).

LC (method A) rt=12.19 min

LC (method B) rt=11.30 min

M.p.=165° C.

EXAMPLE 15

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide(Isomer 1)

APCI-MS: m/z 639 [MH+]

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (1H, d), 8.71 (1H, d), 8.24 (1H, s),8.19 (1H, m), 7.89 (1H, d, further coupled), 7.85 (1H, d, furthercoupled), 7.78 (1H, d), 7.66 (1H, t), 7.72 (1H, dd), 7.13 (1H, d), 7.02(1H, d), 6.98 (1H, dd), 6.86 (1H, s), 5.26-5.17 (3H), 4.82 (2H, s), 4.66(1H, sext.), 4.19 (1H, sext.), 3.54 (1H, dd), 3.01-2.86 (2H), 2.70 (1H,ddd), 2.59-˜2-48 (1H, m, partially obscured by solvent signal),2.43-2.34 (1H, m), 1.56 (3H, t), 1.30 (3H, d).

HPLC method (A): rt=10.65 min

HPLC method (B): rt=9.99 min

M.p.=196° C.

EXAMPLE 16

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide(Isomer 2)

APCI-MS: m/z 639 [MH+]

1H NMR (400 MHz, DMSO-d₆) δ 8.74-8.67 (2H), 8.15 (1H, m), 7.89 (1H, d,further coupled), 7.84 (1H, d, further coupled), 7.77 (1H, d), 7.66 (1H,t), 7.22 (1H, dd), 7.13 (1H, d), 7.02 (1H, d) 6.98 (1H, dd), 6.86 (1H,s), 5.26-5.17 (3H), 5.01 (1H, sext.), 4.82 (2H, s), 4.19 (1H, sext,further coupled), 3.22 (1H, dt), 3.06 (2H, d), 2.82-2.74 (1H), 2.57 (1H,m), 2.14 (1H, m), 1.56 (3H, t), 1.30 (3H, d).

LC (method A): rt=10.40 min

LC (method B): rt=9.67 min

M.p.=202° C.

EXAMPLE 17

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide

APCI-MS: m/z 627 [MH+]

1H-NMR (DMSO-d6, 400 MHz); δ 9.22 (1H, t); 8.71 (1H, d); 8.24 (1H, s);8.21 (1H, t); 7.89 (2H, dd); 7.79 (1H, d); 7.66 (1H, t); 7.32-7.31 (4H,m); 7.28-7.20 (2H, m); 7.13 (1H, d); 7.02-6.96 (2H, m); 6.86 (1H, s);5.23-5.18 (3H, m); 4.82 (2H, s); 4.51 (2H, d); 4.22-4.15 (1H, m); 1.55(3H, t); 1.30 (3H, d).

LC (method A) rt=14.42 min

LC (method B) rt=13.2 min

M.p.=174° C.

EXAMPLE 18

3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2S)-2-hydroxycyclopentyl]benzamide

APCI-MS: m/z 621 [MH+]

1H NMR (400 MHz, DMSO-d₆) δ 8.71 (1H, d), 8.39 (1H, d), 8.24 (1H, s),8.17-8.14 (1H, m), 7.89-7.82 (2H, m), 7.76 (1H, d), 7.64 (1H, t), 7.22(1H, dd), 7.13 (1H, d), 7.04-6.96 (2H, m), 6.86 (1H, s), 5.25-5.18 (3H,m), 4.82 (2H, s), 4.78 (1H, d), 4.24-4.13 (1H, m), 4.06-3.97 (2H, m),2.06-1.96 (1H, m), 1.90-1.80 (1H, m), 1.71-1.42 (7H, m), 1.30 (3H, d).

LC (method A) rt=11.98 min

LC (method B) rt=11.21 min

M.p.=187° C.

EXAMPLE 19

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide

APCI-MS: m/z 655 [MH+]

1H NMR (400 MHz, DMSO-d₆) δ 1.29 (3H, d), 1.55 (3H, t), 2.18-2.29 (1H,m), 2.41-2.49 (1H, m), 3.10 (1H, dd), 3.15-3.26 (1H, m), 3.29-3.42 (1H,m), 3.52 (1H, dd), 4.11-4.23 (5H, m), 4.72 (1H, dd), 5.17 (1H, d),6.78-6.82 (1H, m), 6.84-6.89 (2H, m), 7.14 (1H, d), 7.21 (1H, dd), 7.68(1H, t), 7.77 (1H, d), 7.85 (1H, d), 7.89-7.93 (1H, m), 8.18 (1H, t),8.25 (1H, d), 8.65 (1H, d), 8.90 (1H, d).

LC (method A) rt=10.31 min

LC (method B) rt=9.90 min

M.p.>150° C.

EXAMPLE 20

3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide

APCI-MS: m/z 621 [MH+]

1H NMR (400 MHz, DMSO-d₆) δ 1.30 (3H, d), 1.55 (3H, t), 2.30-2.42 (1H,m), 2.45-2.54 (1H, m), 4.11-4.24 (5H, m), 4.25-4.33 (1H, m), 4.43 (1H,td), 4.77-4.85 (1H, m), 5.17 (1H, d), 6.79-6.82 (1H, m), 6.84-6.89 (2H,m), 7.14 (1H, d), 7.22 (1H, dd), 7.69 (1H, t), 7.79 (1H, d), 7.86 (1H,d), 7.94 (1H, dd), 8.19 (1H, t), 8.26 (1H, d), 8.65 (1H, d), 9.17 (1H,d).

LC (method A) rt=10.4 min

LC (method B) rt=9.92 min

M.p.=183° C.

Biological Experimental Human Glucocorticoid Receptor (GR) Assay

The radioligand GR binding assay is based on a competition assay using^(3H)-labeled Dexamethasone. Dexamethasone is known to bind in theligand binding domain of GR and compete for binding with endogenousligands like e.g. cortisol (Necela, 2003).

In the GR radioligand binding assay, test compounds were seriallydiluted in semi-log steps (10 concentrations) with a final concentrationof 10 μM. Test compounds (1 μL) and controls (1 μL) in 100% DMSO wereadded to 96 Greiner V-bottom polypropylene plates. 0% control was 6.7%DMSO (final concentration in assay) and 100% control was 6.7 μMDexamethasone.

The full length GR was diluted to a final concentration of 3.3% (0.495mg/ml) in assay buffer (20 mM Tris-HCl, 1 mM EDTA, 10% (w/v) Glycerol,20 mM Sodium molybdate, pH 7.4). 45 μL of GR was added to each well andthe plates were incubated for 15 min at room temperature.

^(3H)-dexamethasone solution was diluted to a concentration of 70 nM inassay buffer (7 nM final assay concentration) and 5 μL was added to eachwell. The samples were mixed for 5 min using a plate shaker at 700 rpm,before incubation for 2 h at room temperature. 50 μL ice-cold charcoalsolution (pH 7.4:2% Charcoal, 0.2% Dextran T70 in 20 mM Tris-HCl, 1 mMEDTA and 20 mM Sodium molybdate) was added to each well and the sampleswere mixed on plate shaker for 5 minutes.

The plate was then centrifuged for 1.5 min at 1500 rpm, the samples (80μL) were transferred from each well to a filter plate (Millipore, 0.45μm, MHVBN45) on a vacuum manifold and then collected into new plates(Greiner, 96 well white/transparent, 655095). The filter plate waswashed once with 20 μl of water and then 100 μL of scintillation liquidwas added to each well and mixed by incubation on plate shaker for 5min. Radioactivity was measured in a 1450 Microbeta Trilux Reader(Wallac) counting cpm for 2 minutes per well. The data obtained fromeach replicate experiment were analysed using the software ActivityBase,version 5.4.3 (ID Business Solutions Ltd) and IC₅₀ values werecalculated. Ref: Necela, B M, Cidlowski, J A, Trends Pharmacol Sci, 24:58, 2003

Transrepression Reporter Gene Assay

The human bronchogenic carcinoma cell-line, ChaGo-K-1 (ATCC: HTB 168),were transfected with 5×TRE-LacZ (clone 16:15:5 s5), i.e. TREtransfected cells, to measure transrepression activity of the selectedcompounds. Before use, the cells were grown for one to two weeks inselection medium containing 0.7 mg geneticin (G418)/ml medium. The cellswere cultured at 37° C., 5% CO₂ and 100% humidity in 96 well microtiterplates in RPMI-medium complemented with 10% fetal calf serum, 1%non-essential amino acids and 1% sodium pyruvate. The cells werepassaged once weekly.

The TRE transfected cells were seeded in 96 well plates with 25-30 000cells/well and grown for 72-96 h, to reach about 80% confluence. Tostimulate the upregulation of the AP-1/TRE-activity, the cells werestimulated with 10 ng/ml Phorbol Myristate acetate (PMA) 3-5 h prior toaddition of compounds. The PMA was present during the whole experiment.The TRE mediated effects (transrepression) in the transfected ChagGo-K-1cells was measured as downregulation of (3-galactosidase activity. Theβ-galactosidase activity for the transrepression experiments wasmeasured by a fluorometric assay performed in microtiter plates. Cellswere washed once in PBS. 180 μl of a reaction mixture containing 5 partsof Z-buffer and one part 4-methylumbelliferyl-β-D-galactosidase(MUG)-solution was then added (150 μl Z-buffer [18 μl 0.6 M Na₂HPO4, 12μl 0.6 M NaH₂PO4, 7.2 μl 0.25 M KCl, 18 μl 0.01 M MgSO4, 1.8 μl 10%Triton X-100, 93 μl H₂O]+30 μl 3 mM4-methylumbelliferyl-β-D-galactosidase). After 60 min incubation at 37°C., 70 μl stop buffer was added to each well and the fluorescence wasread in a fluorometer (Spectramax Gemini) with emissionfilter at 460 nmand excitationfilter at 360 nm. The TRE activity was calculated as therelative activity compared to cells not treated with compounds.Inhibition of β-galactosidase by the compounds is expressed as percentinhibition compared to Dexamethasone 10⁻⁶M set as a 100 percent controlwithin each experiment and DMSO 0.1% set as background control. Theeffect of Dexamethasone is well documented in this system and wastherefore chosen as a positive control for comparison of the potency andefficacy of the compounds.

TABLE 1 Binding data, melting point and crystallinity for theexamplified compounds. GR Hu Bind Max Melting Filter Onset Example MeanControl Temperature Agonism TRE Nr IC50 [nM] (° C.) Crystallinity IC50[nM] 1 1.32 180 Crystalline 0.212 2 1.36 218 Crystalline 0.163 3 1.60239 Crystalline 0.344 4 1.40 224 Crystalline 0.733 5 1.08 175Crystalline 0.0514 6 0.913 177 Crystalline 0.0518 7 1.30 170 Crystalline0.163 8 0.796 182 Crystalline 0.388 9 1.09 192 Crystalline 0.191 100.647 165 Crystalline 0.112 11 2.15 182 Crystalline 0.517 12 0.767 135Crystalline 0.0367 13 0.817 159 Crystalline 0.0238 14 1.75 165Crystalline 0.145 15 3.64 196 Crystalline 0.499 16 4.27 202 Crystalline0.6 17 0.996 174 Crystalline 0.754 18 3.44 187 Crystalline 0.552 190.663 >150 Crystalline 0.159 20 1.96 183 Crystalline 0.92

1. A compound of formula Ib:

wherein: A is C₁₋₄alkyl, C₁₋₄alkoxy or C₁₋₄haloalkyl; R³ isC₅₋₁₀heteroaryl; W is phenyl substituted by —C(O)NR⁷R⁸; R⁷ is hydrogenor C₁₋₄alkyl; R⁸ is selected from hydrogen, C₁₋₆alkyl (optionallysubstituted by one or two groups selected from hydroxyl, C₅₋₁₀aryl andC₅₋₁₀heteroaryl), C₃₋₇ cycloalkyl (optionally substituted by hydroxyl),and C₅₋₁₀heterocyclyl (optionally substituted by one or two groupsselected from hydroxyl and oxo); or a pharmaceutically acceptable saltthereof.
 2. The compound according to claim 1, wherein: A isC₁₋₂haloalkyl; R³ is C₅₋₁₀heteroaryl; W is phenyl substituted by—C(O)NR⁷R⁸; R⁷ is hydrogen; R⁸ is selected from C₁₋₄alkyl (optionallysubstituted by hydroxyl, C₅₋₆aryl and C₅₋₆heteroaryl), C₅₋₆cycloalkyl(optionally substituted by hydroxyl), and C₅₋₆heterocyclyl (optionallysubstituted by oxo); or a pharmaceutically acceptable salt thereof. 3.The compound according to claim 1 or 2, wherein A is fluoromethyl,difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl,trifluoroethyl, fluoropropyl, difluoropropyl or trifluoropropyl
 4. Thecompound according to claim 1 or 2, wherein: A is C₁₋₂haloalkyl; R³ isC₅₋₁₀heteroaryl; W is phenyl substituted by —C(O)NR⁷R⁸; R⁷ is hydrogen;R⁸ is selected from C₁₋₄alkyl (optionally substituted by hydroxyl,C₅₋₆aryl and C₅₋₆heteroaryl), C₅₋₆cycloalkyl (optionally substituted byhydroxyl), and C₅₋₆heterocyclyl (optionally substituted by oxo); or apharmaceutically acceptable salt thereof.
 5. The compound according toany one of claims 1 to 4, wherein R⁸ is selected from any one ofdioxidotetrahydrothiophen-3-yl], oxidotetrahydrothiophen-3-yl],tetrahydrofuran-3-yl, oxotetrahydrofuran-3-yl], cyclopentyl,hydroxycyclopentyl], hydroxybutyl, pyridin-4-ylmethyl,pyridin-3-ylmethyl, phenylmethyl.
 6. The compound selected from thegroup of3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide(E1),3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[1,1-dioxidotetrahydrothiophen-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-tetrahydrofuran-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-tetrahydrofuran-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3RS)-tetrahydrofuran-3-yl]benzamide,3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[tetrahydrofuran-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-tetrahydrofuran-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-tetrahydrofuran-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-tetrahydrofuran-3-yl]benzamide,3-[5-({1-(4H-1,3-Benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[tetrahydrofuran-3-yl]benzamide,N-cyclopentyl-3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,N-cyclopentyl-3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-cyclopentylbenzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-cyclopentylbenzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(1R)-2-hydroxycyclopentyl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(2S)-2-hydroxycyclopentyl]benzamide,3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[2-hydroxycyclopentyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2S)-2-hydroxycyclopentyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2R)-2-hydroxycyclopentyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1S,2S)-2-hydroxycyclopentyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(1R,2R)-2-hydroxycyclopentyl]benzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[2-hydroxycyclopentyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2R)-2-hydroxybutyl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(2S)-2-hydroxybutyl]benzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[2-hydroxybutyl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide,3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}1-1H-indazol-1-yl)-N-(pyridin-3-ylmethyl)benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-(pyridin-3-ylmethyl)benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3S)-1-oxidotetrahydrothiophen-3-yl]benzamide(Isomer 1),3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3R)-1-oxidotetrahydrothiophen-3-yl]benzamide(Isomer 2),3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[(3RS)-1-oxidotetrahydrothiophen-3-yl]benzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-[1-oxidotetrahydrothiophen-3-yl]benzamide,3-[5-({(1R,2S)-1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide,3-[5-({1-(4H-1,3-benzodioxin-7-yl)-2-[(2,2-difluoropropanoyl)amino]propyl}oxy)-1H-indazol-1-yl]-N-benzylbenzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3R)-2-oxotetrahydrofuran-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3S)-2-oxotetrahydrofuran-3-yl]benzamide,3-(5-{[(1R,2S)-2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[(3SR)-2-oxotetrahydrofuran-3-yl]benzamide,and3-(5-{[2-[(2,2-difluoropropanoyl)amino]-1-(2,3-dihydro-1,4-benzodioxin-6-yl)propyl]oxy}-1H-indazol-1-yl)-N-[2-oxotetrahydrofuran-3-yl]benzamide,or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising a compound according to any one of claims 1 to 6,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable adjuvant, diluent or carrier.
 8. A compound according to anyone of claims 1 to 6, or a pharmaceutically acceptable salt thereof, ora pharmaceutical composition according to claim 7, for use in therapy.9. The use of a compound according to any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition according to claim 6, in the manufacture of a medicament forthe treatment of a glucocorticoid receptor mediated disease state. 10.The use of a compound according to any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of inflammatory conditions.
 11. The use ofa compound according to any one of claims 1 to 6, or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for thetreatment of respiratory conditions.
 12. The use of a compound accordingto any one of claims 1 to 6, or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment of asthma.13. The use of a compound according to any one of claims 1 to 6, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of COPD.
 14. A method of treating aglucocorticoid receptor mediated disease state, inflammatory condition,a respiratory condition, asthma and/or COPD in a mammal, which comprisesadministering to a mammal in need of such treatment an effective amountof a compound according to any one of claims 1 to 6, or apharmaceutically acceptable salt thereof.
 15. A combination of acompound according to any one of claims 1 to 6, or a pharmaceuticallyacceptable salt thereof, and one or more agents selected from the listcomprising: a PDE4 inhibitor; a selective β.sub2. adrenoceptor agonist;a muscarinic receptor antagonist; a modulator of chemokine receptorfunction; an inhibitor of p38 kinase function; an inhibitor of matrixmetalloproteases, for example targeting MMP-2, -9 or MMP-12; or aninhibitor of neutrophil serine proteases, for example neutrophilelastase or proteinase 3.